Systematic Review of glucose transporter alterations in human Alzheimer’s disease and rodent Alzheimer’s disease models

Systematic Review of glucose transporter alterations in human Alzheimer’s disease and rodent Alzheimer’s disease models | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Systematic Review of glucose transporter alterations in human Alzheimer’s disease and rodent Alzheimer’s disease models Eva Hede, Annette Burkhart, Blanca I. Aldana, Kristi A. Kohlmeier, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7374065/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The brain requires a constant glucose supply to fuel energy production for numerous cellular functions. Glucose is transported into the brain by means of specialized glucose transporter proteins (GLUTs), which ensure transport across the blood-brain barrier (BBB) and uptake in neurons and glia. Dysregulation of brain glucose metabolism has been implicated in contributing to neurodegenerative diseases, including Alzheimer's Disease (AD). While development of neuronal amyloid-beta plaques and tau-containing tangles both occur in AD, recent research suggests that metabolic changes, including GLUT alterations, could play a crucial role in disease progression. This review investigates alterations in GLUT expression occurring in AD patients and related rodent models of AD. Reduction of GLUT1 and GLUT3, key transporters for glucose transport across the BBB and cellular uptake in the brain, was consistently observed in AD patients. These alterations were associated with AD pathology and cognitive decline in several studies. While most rodent studies replicate the findings in human AD, others discern diverse results, highlighting the complexity of AD modeling in laboratory animals. This was further supported by our own original data showing divergent GLUT1 mRNA and protein alterations in Tg-SwDI and 5xFAD mice. GLUT2 and GLUT4 have been less studied, but studies in AD patients suggest an increase in GLUT2 expression, whereas a possible correlation between AD and GLUT4 is absent. Results from studies of GLUT2 and GLUT4 expression in rodent models of AD were too inconsistent to make any clear conclusions. Contributing to the complexity of GLUT's role in AD pathophysiology, rodent studies suggest that GLUT1 deficiency not only contributes to but also exacerbates AD progression by further restricting glucose transport to the brain, leading to intensified metabolic impairments. Together, these findings support that restoring the expression of GLUTs denotes a potential therapeutic target for limiting disease progression in AD. However, due to the divergent results across various studies, it is challenging to draw definitive conclusions regarding GLUT expression in rodent AD models. Some models may not fully replicate the GLUT and metabolic changes observed in AD, posing a limitation that is crucial to consider in future studies to enhance their translational potential. Alzheimer’s disease glucose transporters brain metabolism Alzheimer's disease models Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Glucose is the main energy source of the brain, which requires a constant energy supply to support vital functions such as protein synthesis, maintenance of membrane potentials, and neurotransmission [ 1 – 3 ]. As the local energy stores are limited to minimal glycogen stores in astrocytes, the transport of glucose from the circulation to the central nervous system (CNS) is essential for normal neurological function (Brown & Ransom, 2007; Shah et al., 2012; Sorg & Magistretti, 1991). Unlike most tissues in the body, the brain has a tightly controlled barrier called the blood-brain barrier (BBB) that restricts the free movement of nutrients from the blood into the brain tissue [ 4 , 5 ]. In consequence, the brain relies on specialized transporter proteins to ensure sufficient glucose transport into the brain. Glucose uptake from the blood takes place via facilitative transport through the glucose transporter 1 (GLUT1) [ 4 , 6 – 8 ]. The endothelial cells of the brain form the BBB and express the 55 kDa isoform of GLUT1 at both the luminal and abluminal membrane, while astrocytic end-feet, which line the abluminal side of the endothelial cells, express a 45 kDa GLUT1 isoform (Abbott et al., 2009; Simpson et al., 2007). Due to the constant energy consumption of the brain, the concentration gradient drives the facilitative diffusion of glucose towards the CNS, matching the level of neuronal activity and energy use [ 10 , 11 ]. Within the brain, glucose is taken up by astrocytes via GLUT1 or GLUT2 and transported to neurons or directly taken up by neurons via GLUT3 [ 10 , 12 , 13 ]. Intracellularly, glucose is phosphorylated by hexokinase, converted to pyruvate through glycolysis, and used for ATP generation [ 14 , 15 ]. Astrocytes play a significant role in the transport of glucose within the brain, as they are capable of transporting glucose to the neurons, which is dependent on neuronal activity [ 10 ]. Moreover, astrocytes are capable of releasing lactate, a byproduct of glycolysis, into the extracellular space, where it is accessible for neuronal uptake and subsequent conversion to pyruvate for use in energy production (Stobart & Anderson, 2013). In hypoglycemia, resulting from e.g., fasting, where blood glucose levels drop significantly, the brain can utilize lactate and ketone bodies as alternative energy sources (S. C. Cunnane et al., 2016; Henderson, 2004; Lin et al., 2015). These are transported to the brain via monocarboxylate transporters expressed by brain capillary endothelial cells and astrocytes [ 9 , 20 ]. Contrary to the glucose uptake, the brain uptake of ketone bodies is regulated by the ketone concentration in blood and does not relate to the brain energy consumption [ 17 , 21 , 22 ]. Alterations and dysregulations of brain glucose metabolism have been linked to several neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis, Parkinson’s disease, and multiple sclerosis, which strongly emphasizes the importance of normal functioning of glucose metabolism for the brain [ 23 – 26 ]. AD is the most common cause of dementia with an estimated prevalence of 10 % in pople aged 65 or older ("2020 Alzheimer's Disease Facts and Figures,"2020; Hebert et al., 2013). AD is characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Approximately 5 % of A cases are directly attributable to genetic factors, while the majority are sporadic, with unknown causes of disease development. Over the past decades, one of the most extensively studied AD mechanisms is the amyloid cascade hypothesis, which states that neurodegeneration observed in AD is caused by the accumulation of Aβ plaques in various areas of the forebrain [ 27 – 30 ]. According to this hypothesis, abnormal cleavage of the amyloid precursor protein (APP) by β- and γ-secretase through the amyloidogenic pathway leads to the accumulation of Aβ peptides forming beta-sheets, which assemble into oligomers and fibrils forming the Aβ plaques, which are believed to cause neuroinflammation, neuronal dysfunction, tau hyperphosphorylation, and formation of reactive oxygen species ultimately leading to neuronal cell death and brain atrophy [ 31 – 39 ]. However, a growing amount of evidence demonstrates that the Aβ plaque load does not correlate completely with the clinical severity of the disease, as Aβ plaques can also be observed in healthy elderly individuals [ 40 – 42 ]. Furthermore, recently approved anti-Aβ antibody treatments, capable of inducing significant clearance of Aβ, only partially slow disease progression [ 40 – 47 ]. An alternative to the amyloid cascade hypothesis is the tau hypothesis, which argues that abnormal hyperphosphorylation of tau protein, resulting from the formation of NFTs, is the trigger of AD development [ 48 ]. While the tau hyperphosphorylation and NFT formation possibly correlate better with the clinical score, halting disease progression has not yet been achieved in clinical studies through Aβ or tau targeting [ 43 – 45 , 49 , 50 ]. Metabolic changes, involving glucose hypometabolism and mitochondrial dysfunction, are both characteristics of AD [ 26 , 51 – 53 ]. These changes have traditionally been considered consequences of neuronal loss and brain atrophy [ 27 ]. However, reduced brain glucose uptake has also been found by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in people with an increased risk of developing AD both with and without mild cognitive impairment (MCI), indicating that the metabolic changes precede the development of neuronal dysfunction and brain atrophy (Mosconi et al., 2009, 2013; Protas et al., 2013). Reductions in the cerebral metabolic rate of glucose CMR glc could be detected by FDG-PET up to 7 years before developing clinical AD [ 54 ]. Additionally, hypometabolism, but not atrophy, precedes in the precuneus and posterior cingulate cortex in patients with MCI and AD [ 58 ], demonstrating that hypometabolism in AD takes place before the development of brain atrophy and neurological symptoms. Moreover, AD progression increases in patients with hypometabolism following FDG-PET analysis of 551 AD patients, which further emphasizes that hypometabolism plays an important role in the development of AD [ 57 ]. It is currently far from understood what triggers hypometabolism in AD. Decreased levels of GLUT1 at the BBB have been observed in AD patients and the amount of GLUT1 in brain endothelial cells has been shown to correlate with glucose uptake in the brain, demonstrating the essential role of GLUT1 expression for brain glucose uptake [ 59 – 64 ]. Moreover, GLUT1 deficiency syndrome, a rare genetic metabolic disease caused by GLUT1 haploinsufficiency, is associated with several neurological symptoms including cognitive impairment and microencephaly in humans [ 65 , 66 ]. Furthermore, it has been suggested that GLUT1 is involved in the regulation of BBB integrity as studies in zebrafish have demonstrated an essential role of GLUT1 in BBB development [ 67 – 69 ]. Thus, GLUT1 protein expression and thereby GLUT1-mediated brain glucose uptake could play a significant role in the development of AD. In transgenic mice overexpressing human APP crossed with GLUT1-deficient mice, GLUT1 deficiency accelerated the progression of AD [ 70 ]. In addition, GLUT1 overexpression induced neuroprotection in a Drosophila model of AD (Niccoli et al., 2016), further emphasizing that GLUT1 expression plays a significant role in AD development. Previous reviews on GLUT alterations and hypometabolism in AD suggested GLUT1 and other brain GLUTs as potential therapeutic targets in AD [ 62 , 72 ]. GLUT alterations were previously reviewed by Szablewski and Kyrtata, who suggested decreased expression of in human AD studies [ 62 , 63 ]. However, AD development and potential treatments are still widely studied in animal models, where the alterations in brain GLUTs vary between different models and analyses. While several studies report reduced expression of GLUTs in rodent models of AD [ 62 , 73 – 76 ], other studies were unable to find alterations in the expression of one or more GLUTs when compared to wild-type controls [ 70 , 77 – 80 ]. Moreover, an increasing amount of evidence suggests an incomplete causal link between Aβ plaque load and clinical symptoms in AD, which has increased the interest in exploring the metabolic changes associated with disease development [ 43 – 47 ]. As GLUT1 expression has been directly linked to AD progression, this study provides an updated review of GLUT changes in AD patients and in AD rodent models through a systematic review based on analyses of the current literature, with additional analysis of GLUT1 expression in the 5xFAD and Tg-SwDI AD mouse models. Moreover, this review focuses on how GLUT alterations observed in AD patients are replicated in animal models of the disease. Methods Systematic review A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [ 81 ]. The search strategy focused on articles with the combined mention of “glucose transporter proteins, facilitative”, “glucose transporter”, or “GLUT” and “Alzheimer Disease”, “Alzheimer’s disease”, or ”Alzheimers Disease”. It was based on a combined Title/abstract and MeSH or Emtree search in Pubmed or Embase, respectively, as specified in Table 1 . Table 1 Applied search strategies for the systematic literature review. Database Search strategy Date Pubmed ((("glucose transport proteins, facilitative"[MeSH Terms]) OR (glucose transporter[Title/Abstract])) OR (GLUT[Title/Abstract])) AND (((("Alzheimer Disease"[Mesh]) OR (alzheimer disease[Title/Abstract])) OR (alzheimer's disease[Title/Abstract])) OR (alzheimers disease[Title/Abstract])) July 1st 2025 Embase ('glucose transporter'/exp OR 'glucose transporter':ti,ab,kw OR 'glut':ti,ab,kw) AND ('alzheimer disease'/exp OR 'alzheimer disease':ti,ab,kw OR 'alzheimers disease':ti,ab,kw) July 1st 2025 Inclusion and exclusion criteria are presented in the PRISMA flowchart (Fig. 1 ). Identified articles were imported into Mendeley Reference Manager, where duplicates were identified and excluded. Studies were then screened manually by the first author based on titles and abstracts and excluded in cases where CNS GLUT expression was not analyzed or compared to healthy controls, or if the study was not performed in AD patients or animal models of AD. In vitro studies were excluded as this review focuses on GLUT alterations in AD patients and animal models. Finally, reviews and conference abstracts were excluded. Studies were included for further assessment when it was impossible to determine eligibility based on title and abstract. The remaining articles were then retrieved and assessed for eligibility. Again, studies were excluded according to the exclusion criteria described above, and the final studies were included as either human or rodent studies. Glut1 gene expression analysis in Tg-SwDI and 5xFAD mice Relative Glut1 mRNA gene expression was analyzed using multiplex probe-based RT-qPCR. RNA was purified from cortical samples from 24-month-old Tg-SwDI mice of mixed sexes (n = 6), 4-month-old female 5xFAD mice (n = 8), and female wild-type littermates as controls (n = 6–8), using NucleoSpin TriPrep DNA, RNA, and Protein purification kit (Macherey-Nagel, #740966.50), according to the manufacturer's protocol. Briefly, the samples were homogenized with RP1 buffer supplemented with 1% β-mercaptoethanol and filtered through a column filter, followed by the addition of 70% ethanol to bind nucleic acids to a DNA and RNA-binding silica membrane. The membrane was then washed two times with DNA Wash, followed by centrifugation, dried, and incubated for 1 min with DNA Elute, followed by centrifugation to elute DNA. Residual DNA was subsequently digested on the column by the addition of a DNase reaction mixture and 15 min incubation at room temperature. Finally, the silica membrane was washed twice with wash buffer RA2 and RA3, followed by a final wash with wash buffer RA3 and subsequent membrane drying to enable RNA elution with RNase-free H 2 O. Purified RNA was subsequently used as the template for cDNA synthesis with Maxima H Minus First-strand cDNA Synthesis Kit (Thermo Fisher Scientific, #K1651), according to the manufacturer's protocol. In brief, 100 ng RNA was used for the cDNA synthesis reaction with 25 pmol oligo(dT)18 and random hexamer primers, 0.5 mM dNTP Mix, and Maxima H Minus Enzyme Mix in RT buffer. The reaction was incubated in a Veriti™ 96-Well Thermal Cycler (Applied Biosystems) with 10 min primer annealing at 25°C followed by polymerization at 50°C for 30 min and termination at 85°C for 5 min. The RT-qPCR reaction was performed using TaqMan Fast Advanced Master Mix (Thermo Fisher Scientific, #4444556), FAM conjugated mouse GLUT1 primer-probe mix (Thermo Fisher Scientific, #4331182, assay ID: Mm00441480_m1), VIC conjugated mouse HPRT1 primer-probe mix (Thermo Fisher Scientific, #4448489, assay ID: Mm03024075_m1), and 5 ng sample cDNA as template, according to the manufacturer's protocol. The reaction was initiated with uracil-N-glycosylase digestion at 50°C for 2 min, to remove potential DNA contaminates, followed by denaturation at 95°C for 2 min and 40 cycles of denaturation for 1 s at 95°C and annealing/extension for 2 min at 60°C on a QuantStudio 6 Flex Real-Time PCR System (ThermoFischer Scientific). Relative gene expression was calculated according to the ΔΔCt method [ 82 ] based on the obtained threshold cycle (Ct) values using wild-type control samples as the calibrator. GLUT1 protein quantification in Tg-SwDI and 5xFAD mice The brain GLUT1 protein concentrations were examined in cortical samples from 24-month-old Tg-SwDI mice og mixed sexes (n = 6) and whole brain homogenates, cortical brain slices, and hippocampal brain slices from 4-month-old female 5xFAD (n = 6) mice and littermate female wild-type controls (n = 3–6). Protein was purified using N-PER Neuronal Protein Extraction Reagent (Thermo Fisher Scientific, #87792), according to the manufacturer’s protocol. In brief, samples were homogenized in N-PER, supplemented with cOmplete™, Mini, EDTA-free Protease Inhibitor Cocktail (Merk KGaA, #11836170001), incubated on ice for 10 min and centrifuged at 10,000 x g for 10 min at 4°C to pellet debris. Total protein concentrations were subsequently determined in duplicates using Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific #23225) with 562 nm measurements on an EnSpire Multimode Plate Reader (Perkin Elmer). The GLUT1 protein concentration in the brain samples was analyzed by sandwich ELISA, using a mouse GLUT1 ELISA kit (Nordic BioSite, #EKX-68BIK3-96), according to the manufacturer’s protocol. Briefly, protein samples and seven two-fold serial diluted standards ranging from 0.313 to 20 ng/ml were added to primary antibody pre-coated wells and incubated at 37°C for 90 min. The wells were subsequently washed two times, followed by incubation with Biotin-labeled secondary antibody at 37°C for 60 min. Then, wells were washed three times, incubated with HRP-Streptavidin Conjugate at 37°C for 30 min, and subsequently washed five times. Finally, the wells were incubated with TMB Substrate for 20 min at 37°C after which Stop Solution was added followed by OD measurement at 450 nm on an EnSpire Multimode Plate Reader (Perkin Elmer). Samples and standards were all measured in duplicates and the data was subsequently analyzed in GraphPad Prism 10.0.2 using a 4-parameter sigmoidal logistics curve to interpolate the sample concentrations based on the standard curve. Statistics All data sets were initially tested for normality using the Sharpiro-Wilk normality test and for equal variance using an F-test. Data sets for relative gene expression and cortical protein expression in 5xFAD mice (Fig. 2 C + D) did not pass the normality test and were therefore analyzed by the non-parametric Mann-Whitney U test. Homogeneity of variance was not met in the data set for relative gene expression in Tg-SwDI mice, which was therefore also analyzed with the Mann-Whitney U test (Fig. 2 A). The remaining data sets were normally distributed with homogeneity of variance and were therefore analyzed by parametric unpaired two-tailed t-tests (Fig. 2 B, 3 A-B). Results The systematic literature review resulted in 15 human and 45 rodent studies analyzing the expression of GLUTs in AD. Both human and rodent studies exclusively included postmortem studies of different brain regions. The most studied CNS transporter was GLUT1, which was studied in 10 of the 15 human studies and 37 out of the 49 rodent studies. The second most studied transporter was GLUT3, primarily responsible for glucose uptake in neurons. GLUT3 expression was analyzed in seven human and 25 rodent studies. The insulin-dependent neuronal glucose transporter, GLUT4, was studied in a single human study and 13 rodent studies, while the astrocytic glucose transporter, GLUT2, was studied in two human studies and six rodent studies. Finally, a single rodent study examined the more recently discovered GLUT12. While GLUT12 is mainly expressed in peripheral tissues, expression within the brain was demonstrated by RNA sequencing, primarily in oligodendrocyte progenitor cells and astrocytes [ 83 , 84 ]. The expression of GLUT12 has been linked to insulin sensitivity and the development of cancer and diabetes [ 84 ]. However, the function of GLUT12 in the brain remains unclear. Evidence of GLUT alterations from human studies Most human studies analyzing GLUT1 expression observed a reduction in various brain regions, such as the hippocampus and cerebral cortex, in tissue samples obtained from AD patients compared to healthy age-matched controls. An exception quantified GLUT1 in microvessels using immunohistochemistry combined with stereology, which showed an increase in GLUT1 intensity was noted in the hippocampal CA1 region of AD patients when compared to controls, but no differences in the CA2 region were detected [ 85 ]. The alterations in GLUTs reported in the human studies are summarized in Table 2 . Altered GLUT expression in AD was initially discovered by Kalaria and Harik in microvessels, cerebral cortex, and hippocampus by demonstrating reduced H 3 glucose binding as well as reduced levels of hexose transport proteins in human postmortem tissue [ 86 ]. In a subsequent study, Harik et al. found a 50 % reducion in the density of glucose transporters in cerebral microvessels in postmortem tissue from AD patients compared to age-matched controls. This was further supported by subsequent immunolabeling, showing significantly lower GLUT1 intensities in hippocampal tissue from AD patients compared to age-matched controls [ 87 ]. Kawai et al. further demonstrated reduced GLUT1 density related to the presence of Aβ plaques in hippocampal sections of AD patients [ 88 ]. Simpson et al. demonstrated a reduction in both the endothelial GLUT1 and neuronal GLUT3 in cortical AD samples compared to healthy controls [ 89 ], which was consistent with findings by Harr et al. demonstrating a 49.5 % reduction in GLUT immunoreactivity in the hippocampal dentate gyrus in AD brains [ 90 ]. In addition, An et al. demonstrated reduced GLUT3 levels by LC-MS/MS in frontal gyrus tissue from AD patients compared to healthy controls when adjusting for neuronal nuclear protein levels, age at death, and sex [ 91 ]. Their results also demonstrated a correlation between GLUT3 reductions and the severity of Aβ and NFT pathology. The GLUT1 reductions were further confirmed in more recent studies by Wang et al.[ 92 ] and Leclerc et al.[ 93 ]. In the study by Wang et al. GLUT1 expression in the cortex and hippocampus areas, quantified from immunohistochemical staining, was markedly reduced in AD patients compared to controls [ 92 ]. Leclerc et al. analyzed GLUT1 protein levels in microvessel extracts from the parietal cortex by Western Blot and found GLUT1 reductions in AD samples compared to controls, which correlated with the levels of neuritic plaques and cerebrovascular β-secretase-derived fragments. Moreover, they found an association between GLUT1 reductions and cognitive scores [ 93 ]. Mooradian et al. observed a reduction of GLUT1 protein in the cortex of AD brains, whereas the GLUT1 mRNA expression was equal to that in healthy controls, indicating post-transcriptional regulation of GLUT1 expression[ 94 ] Moreover, Jin et al. examined the GLUT3 mRNA expression in the frontal cortex and found reduced mRNA levels in cortical tissue from AD patients compared to age-matched controls[ 95 ] consistent with reduced GLUT3 protein levels found by others [ 89 , 90 , 96 , 97 ]. Unfortunately, Jin et al. did not examine the GLUT3 protein levels, making it difficult to conclude on possible post-transcriptional regulation of GLUT3 expression. Liu et al. analyzed the expression of GLUT1, GLUT2, GLUT3, and GLUT4 in postmortem tissue from AD patients and found significantly decreased GLUT1 and GLUT3, increased GLUT2, and unaltered GLUT4 in tissue from AD patients compared to age-matched controls [ 98 ]. These findings were confirmed in a later study by the same group, demonstrating the expression of GLUT1, GLUT2, and GLUT3 in postmortem tissue from AD patients with or without diabetes mellitus [ 96 ]. They also found a significantly reduced expression of GLUT1 and GLUT3 in AD, while the GLUT2 expression was significantly increased in AD compared to healthy controls. In tissue from AD patients with diabetes mellitus, they also found reduced GLUT3 and increased GLUT2. However, contrary to the reduced expression of GLUT1 in AD patients without diabetes mellitus, the GLUT1 expression was unaltered in AD patients with diabetes compared to controls. Overall, the human studies analyzing GLUT alterations in AD almost consistently observed AD-related reduction in GLUT1 and GLUT3 protein expression analyzed by immunohistochemistry, Western Blotting, and LC-MS/MS in various brain regions, except for a single study finding increased GLUT1 expression in microvessels of the hippocampal CA1 region. Only a single study examined the GLUT2 expression in AD and found an AD-related increase in GLUT2 protein expression. Moreover, results from several studies demonstrate a correlation between the reductions in GLUT1 and GLUT3 protein expression and AD pathology. Table 2 Overview of glucose transporter alterations found in human studies, comparing AD patients to healthy age-matched controls. AD: Alzheimer’s disease, DMT2: Diabetes Mellitus type 2, WB: Western Blot, NB: northern blot, IHC: immunohistochemistry, LC-MS/MS: liquid chromatography with tandem mass spectrometry. Study Samples Methods Subjects Sex GLUT1 GLUT2 GLUT3 GLUT4 Kalaria et al. 1989 Postmortem brain tissue H3 Glucose binding assay 26 AD patients and 23 controls Unreported Reduced Harik et al. 1991 Postmortem cerebral microvessels H3 Glucose binding assay 13 AD patients and 13 controls Unreported Reduced Kawai et al. 1990 Postmortem hippocampus sections IHC 3 AD cases. (No controls) Male Reduced Horwood et al. 1994 Postmortem hippocampal tissue IHC 9 AD patients and 8 controls Mixed Reduced Simpson et al. 1994 Postmortem tissue WB 12 AD patients and 12 controls Unreported Reduced Reduced Harr et al. 1995 Postmortem hippocampal tissue IHC 8 AD patients and 8 controls Unreported Reduced Mooradian et al. 1997 Postmortem cerebral microvessels WB and NB 8 AD patients and 7 controls Mixed Reduced Liu et al. 2008 Postmortem frontal cortex tissue WB 7 AD patients and 7 controls Mixed Reduced Increased Reduced Unaltered Liu et al. 2009 Postmortem frontal cortex tissue WB 10 AD patients, 8 AD + DMT2 patients, and 7 controls Mixed Reduced Increased Reduced Jin et al. 2013 Postmortem frontal cortex tissue qPCR 7 AD patients and 7 controls Mixed Reduced Burke et al. 2014 Postmortem hippocampal tissue IHC 14 AD patients and 13 controls Unreported Increased An et al. 2018 Postmortem brain tissue LC-MS/MS 14 AD patients and 14 controls Mixed Reduced Nam et al. 2023 Postmortem frontal cortex tissue IHC 10 AD patients and 10 controls Mixed Reduced Wang et al. 2022 Postmortem cortical and hippocampal tissue IHC 5 AD patients and 5 controls Mixed Reduced Leclerc et al. 2024 Postmortem parietal cortex tissue WB 20 AD patients, 20 MCI patients, and 20 controls Mixed Reduced Evidence of GLUT alterations in rodent AD models The 50 rodent studies included in this review consisted of 11 studies in five different rat AD models and 39 studies in 13 different mouse AD models. While most mouse studies analyzing the GLUT expressions were performed in transgenic mouse models, the rat studies were mainly performed in sporadic AD models. The rat studies almost consistently revealed reduced GLUT1, GLUT3, and GLUT4 expression and increased GLUT2 expression in AD rats compared to wild-types, while the AD mouse studies found both reduced, increased, and unchanged GLUT1-4 expression. GLUT alterations in mouse models based on the APP transgene Eight of the included mouse studies were performed in transgenic AD models based on the human APP transgene bearing one or more mutations linked to familial AD (Table 3 ). Kouznetsova et al. studied AD-related cerebral cortical capillary changes in Tg2576 AD mice and found reduced cortical GLUT1 capillary density by immunohistochemistry in 18-month AD mice compared to wild-type controls [ 99 ]. These mice overexpress the APP transgene bearing the Swedish mutation under the control of the hamster prion protein promoter and develop synapse loss from 4.5-month-old mice followed by cognitive impairment between 6 and 12 months, gliosis from 10–16 months, and Aβ plaques from 11–13 months [ 100 , 101 ]. Consistent with the initial findings by Kouznetsova et al. a later study by the same group demonstrated reduced GLUT1 expression in 18-month-old Tg2576 mice by immunocytochemistry when Aβ plaque load was considerable, but no changes in GLUT1 at 10 months, which is at the beginning of plaque deposition, indicating that Aβ accumulation may contribute to GLUT1 reductions [ 76 ]. In a different study, Winkler et al. examined the effect of GLUT1 deficiency on the progression of AD development in Tg2576 mice. They did not find any significant differences in cortical and hippocampal GLUT1 protein intensities in presymptomatic 6-month-old Tg2576 mice compared to wild-type controls using immunohistochemistry, further supporting a possible correlation between Aβ pathology and GLUT1 reductions [ 70 ]. However, induced GLUT1 deficiency in the Tg2576 mice, accelerated AD symptoms and pathology, indicating that GLUT1 reduction can also accelerate the Aβ pathology. Combined, these studies indicate that Aβ pathology can affect GLUT1 expression and that reduction of GLUT1 can also accelerate AD pathology. Um et al. and Cho et al. analysed 13-month-old APPsw-NSE mice[ 102 , 103 ] which overexpress the same APP transgene bearing the Swedish mutation as the Tg2576 mice, but under the control of the neuron-specific enolase (NSE) promoter, resulting in the development of Aβ-plaque like depositions already from two months of age, and found significantly reduced GLUT1 expression by Western Blotting found significantly reduced GLUT1 expression by Western Blotting (Hwang et al., 2004; J. H. Kim et al., 2012). Additionally, Shang et al. found reduced cortical GLUT1 intensities in immunohistochemical staining in 12-month-old male APP23 mice based on another APP transgene isoform bearing the Swedish mutation under the control of the murine Thy1 promoter [ 106 ]. These mice present with cognitive impairment as early as three months of age followed by gliosis and amyloid plaques at 6 months and neuronal loss developing around 14–18 months [ 107 – 110 ]. Merlini et al. analyzed cortical and hippocampal GLUT1 and GLUT3 alterations by Western Blotting in 9–13 month-old ArcAβ mice[ 111 ] containing the human APP transgene with the Swedish mutation and an additional Arctic mutation [ 112 ]. At 6 months of age, these mice develop cognitive impairment followed by plaques between 9 and 15 months, and a reduced endothelial GLUT1 expression compared to wild-type littermates was seen, no significant difference in GLUT3 expression was seen between genotypes, contrary to the observations from human AD studies described above [ 111 ]. To support existing findings of GLUT1 expression in AD mouse models, we analyzed Glut1 gene and protein expression in 24-month-old Tg-SwDI mice of mixed sexes with marked pathology and neuroinflammation[ 113 ] and compared these levels to age-matched female wild-type controls. The Tg-SwDI mice express the human transgene for APP with the Swedish mutation along with the Dutch, and Iowa mutations, related to familial cerebral amyloid angiopathy (CAA), under the control of the Thy1.2 promoter [ 114 ]. CAA is an evident feature of AD, defined by the progressive accumulation of Aβ protein within the brain vasculature, leading to an increased risk of hemorrhages [ 115 , 116 ]. These transgenic mice present with Aβ plaques, significant CAA, and cognitive impairment from three months of age, and gliosis at six months of age(Davis et al., 2004; Miao et al., 2005; F. Xu et al., 2007). In contrast to many of the listed studies, we found a significant 22.9-fold increase in cortical Glut1 gene expression (P = 0.0022) and a significant increase in protein concentration from 5.66 ng GLUT1 per mg total protein in wild-types to 7.33 ng GLUT1 per mg protein in Tg-SwDI mice (P = 0.0398) analyzed with enzyme-linked immunosorbent assay (ELISA) (Fig. 2 ). All the results from studies performed in transgenic mouse models based on a mutated human APP gene show an AD-related decrease in GLUT1 expression in whole brain homogenates, cortex, and hippocampus analyzed by Western Blot and immunohistochemistry, possibly following Aβ plaque formation, except for our analysis of the Tg-SwDI mouse which demonstrated a significant increase in cortical GLUT1 gene and protein at 24 months compared to controls, when analyzed by qPCR and ELISA (Fig. 1 A, B). Interestingly, this was also the only study analyzing the GLUT1 expression in an AD model with CAA pathology, which could suggest that the microvessels are affected differently in this case compared to models with primarily parenchymal Aβ deposition. Moreover, the Tg-SwDI mice develop gliosis at 6 months of age(Miao et al., 2005), like the APP23 mice [ 110 ], whereas this does not occur until the age of 10 months in the Tg2576 mice[ 101 ] and was not reported in the APPsw-NSE and ArcAβ mice. When combined with the older age of the Tg-SwDI mice in the present study, the level of gliosis could be markedly higher in these mice, which might contribute to a higher expression of the astrocytic GLUT1 isoform simply due to an increased number of astrocytes or potentially increased expression in activated microglia [ 118 ]. However, this would be inconsistent with the decreased GLUT1 expression observed in postmortem samples from aged human AD patients. Additionally, the present study in Tg-SwDI mice was the only study analyzing the protein concentrations by ELISA, which is characterized by higher accuracy and reliability compared to Western Blots[ 119 ] and likely also more sensitive than quantitative immunohistochemistry, which is generally merely subjective as small differences in exposure time or selected areas for quantification can have a substantial impact on the results [ 120 ]. A disadvantage of the ELISA used in the present study is that both the endothelial and astrocytic GLUT1 isoforms are detected, whereas these can be differentiated on the Western Blots due to the size differences. However, only two of the studies analyzing GLUT1 expression by Western Blot specified that they were quantifying the endothelial 55 kDa isoform [ 102 , 111 ], while the remaining two studies did not specify whether the quantification was based on one or both isoforms [ 74 , 103 ], which makes it difficult to draw any conclusions regarding the possible influence of astrocytic GLUT1 on the reported GLUT1 protein levels. Results regarding the GLUT3 expression in APP-based mouse models were inconsistent, as the two studies investigating GLUT3 expression found an AD-related decrease and unaltered GLUT3 expression when analyzed by Western Blot [ 111 , 121 ]. While the study by Gil-Iturbe et al., demonstrating a reduction in GLUT3 expression, was performed in female mice, the sex of the animals was not reported in the study demonstrating unaltered GLUT3 by Merlini et al. Thus, it is not possible to draw any general conclusions regarding the GLUT3 expression in the APP-based mouse models from these results. GLUT alterations in mouse models based on APP and PSEN1 mutations 16 mouse studies were conducted using transgenic AD models expressing both human APP and the γ-secretase subunit presenilin 1 (PSEN1) genes, with mutations linked to familial AD (Table 3 ). 10 mouse studies examined the expression of CNS glucose GLUTs in the APP/PS1dE9 mouse model containing a chimeric mouse/human APP transgene bearing the Swedish mutation and human PSEN1 lacking exon 9 (dE9) under the control of the mouse prion protein promoter [ 122 ]. These mice exhibit synaptic loss in the hippocampal area starting from 4 months of age, followed by gliosis and Aβ plaque development from 6 months, and neuronal loss at 8 months, culminating in cognitive impairment at 12 months [ 122 – 124 ]. Gil-Iturbe et al. analyzed the cortical expression of both GLUT1, GLUT3, GLUT4, and GLUT12 in 16-month-old female Tg2576 mice and 16-month-old female double transgenic APP/PS1dE9 mice by Western Blot. They observed reduced GLUT1 and GLUT3 expression, increased GLUT12 expression, and unchanged GLUT4 expression in both animal models compared to controls [ 121 ]. While the AD-related GLUT1 reduction observed by Gil-Iturbe et al. was consistent with the findings from human studies and other APP-based mouse models, the decrease in GLUT3 expression was also consistent with the findings from human studies, but contrary to the unaltered expression found by Merlini et al. in the ArcAβ APP mice. In a more recent study, Ma et al. were also able to detect a significantly reduced GLUT1 expression in brain homogenates from 14-month-old male APP/PS1dE9 mice compared to wild-type controls by Western Blot analysis (Ma et al., 2022). Hooijman et al. analyzed the hippocampal GLUT1 protein expression in 8- and 18-month-old APP/PS1dE9 mice by immunohistochemistry [ 126 ], and found significantly reduced GLUT1 protein levels with unchanged capillary density at 18 months but no significant GLUT1 changes at 8 months, compared to controls, even though Aβ plaques and gliosis is present at this age. Thus, these findings conflict with the suggested correlation between Aβ plaque development and GLUT1 reductions. Both Huang et al. and Wang et al. examined the GLUT1 expression in 2-, 4-, and 9-month-old APP/PS1dE9 mice by immunohistochemistry and found a significantly reduced GLUT1 intensity in the hippocampus area at 4 and 9 months compared to controls, but not in 2-month-old mice [ 73 , 92 ]. These findings thus support a possible correlation between GLUT1 reductions and AD pathology, indicating that GLUT1 reduction can precede plaque development in this model, as the Aβ plaques are not present in the 4-month-old mice. Using the same mouse model, APP/PS1dE9, Chen et al. investigated the effects on cognition of the traditional Chinese medicine, Banxia Xiexin decoction and found reduced hippocampal levels of both GLUT1 and GLUT3 by Western Blot in 6-month-old untreated AD mice compared to wild-type controls [ 127 ]. Guo et al. also reported reduced GLUT3 levels in the hippocampus and cortex of 6-month-old APP/PS1dE9 mice compared to controls when examined by immunohistochemistry [ 128 ]. On the contrary, Zerbi et al. did not find any AD-related differences in GLUT1 expression in hippocampal areas in 8- and 12-month-old AD mice, when analyzed by immunohistochemistry [ 129 ] and Zhang et al. did not find any significant difference in the hippocampal GLUT3 expression in 13-month-old APP/PS1dE9 mice when analyzed with Western Blot [ 130 ]. Finally, Khandelwal et al. analyzed the relative gene expression of Glut1, Glut3 , and Glut4 in 8-month-old APP/PS1dE9 mice and found increased relative GLUT1 and GLUT4 expressions in transgenic mice compared to wild-type controls, while there was not any significant difference in the relative Glut3 gene expression [ 131 ]. However, this was the only study examining the gene expression, and the inconsistency with results from other studies examining the protein levels could be due to post-transcriptional regulation. Nevertheless, while six of the eight studies examining GLUT1 expression in the APP/Ps1dE9 model find an AD-related reduction corresponding to the findings from human studies, the results from the studies performed in this model are generally inconsistent regarding the expression of GLUTs and the correlation between this and AD pathology. This could be ascribed to differences in age, sex or brain regions analyzed. The studies reporting increased or no differences in AD-related GLUT1 or GLUT3 expression analyzed hippocampal and whole brain homogenates from 8- to 13-month-old male mice or mice of unreported sex [ 129 – 131 ], while the remaining studies, finding AD-related GLUT1 or GLUT3 reductions analyzed hippocampal, cortical and whole brain homogenates from 4- to 14-month-old male mice or mice of unreported sex [ 73 , 92 , 125 – 128 , 132 ]. It is therefore not possible to explain the inconsistent results between the studies by differences in age, sex or brain regions analyzed. On the contrary, all studies, except one, analyzed the protein expression levels based on immunohistochemistry or Western Blots, which are associated with a higher variability between tests compared to ELISA for protein quantification [ 119 ]. The inconsistent results from studies in the APP/Ps1dE9 model make it difficult to draw any clear conclusions regarding the expression of GLUTs in this model and how this would correlate with the findings from human studies. Six of the 39 mouse studies analyzed the expression of GLUT in the APP/PS1 mouse model. These mice contain the human APP transgene bearing the Swedish mutation and the human PSEN1 transgene bearing an L166P mutation under the control of the Thy1 promotor. These mice develop Aβ plaques and gliosis from 6 weeks of age in the cortex and at 3 months in the hippocampus, synaptic loss at 10 weeks, cognitive impairment at 7 months, and neuronal loss in areas with high neuronal density at 17 months [ 133 – 135 ]. Pang et al. and Qin et al analyzed the expression of GLUT1 and GLUT3 by Western Blot in male APP/PS1 mice [ 136 , 137 ] and described reduced GLUT1 and GLUT3 levels in the cortex and hippocampus of 8-month-old mice and the hippocampus of 6-month-old mice, respectively. These findings were consistent with results from a study by Wu et al. investigating the effects of progesterone on neuronal glucose. They found significantly reduced GLUT3 and GLUT4 protein levels in the cortex of 6-month-old male untreated APP/PS1 mice compared to wild-type controls using both immunocytochemistry and Western Blot [ 138 ]. Moreover, Wang et al. investigated the effect of the traditional Chinese medicine Jiaotaiwan on brain glucose metabolism in 3-month-old male APP/PS1 mice. They demonstrated reduced GLUT1, 3, and 4 gene and protein expression in cortex and hippocampus of AD mice compared to wild-type controls, when analyzed by Western Blot and qPCR [ 139 ]. On the contrary, a fourth study by He et al. showed no significant difference between the hippocampal GLUT1, 3, or 4 expressions in 6-month-old male APP/PS1 mice and wild-type controls when analyzed by Western Blotting [ 77 ]. Conversely, they found a significantly increased GLUT1 and GLUT3 expression in the APP/PS1 mice with diabetes mellitus, induced by intraperitoneal streptozotocin (STZ) injection, compared to untreated APP/PS1 mice, implicating the role of insulin on GLUT1 regulation, which was also observed in humans by Liu et al [ 96 ]. Qi et al. examined the effects of age and sex on hypothalamic glucose alterations in APP/PS1 mice [ 140 ]. Consistent with the findings by He et al., they demonstrated unchanged GLUT3 expression in AD mice compared to wild-type controls. However, they observed an increased GLUT1 expression in 3-month-old AD males and 14-month-old AD females, when compared to age-matched controls, while the GLUT1 expression was unaltered in 14-month-old males and 3-month-old females [ 140 ]. The inconsistency in observed GLUT1, GLUT3, and GLUT4 expressions could not be explained by variations in model, age, sex, brain region, or analysis method in this case, as both He et al. and Qin et al. analyzed hippocampal tissue in 6-month-old male mice by Western Blot with different results. However, the quantification of GLUT protein levels was based on brain tissue from three mice in the study by He et al., while tissue from five, six, and 12 mice was used for quantification in the studies by Pang et al., Qin et al., and Wu et al., respectively [ 77 , 136 – 138 ]. Thus, the studies finding an AD-related reduction in the expression of GLUTs likely had a greater sensitivity to detect differences when compared to the study by He et al. Moreover, in the study by He et al., the GLUT protein levels were normalized to GAPDH protein levels, while beta-actin protein levels were used for normalization in the other studies performed in APP/PS1 mice. These parameters, combined with relatively lower reliability between experiments of Western Blots compared to other methods for protein quantification, could perhaps explain the inconsistencies in observed GLUT1, GLUT3, and GLUT4 expression in the APP/PS1 model. To sum up, three of the four studies investigating GLUT expression in APP/PS1 mice found reduced GLUT1, GLUT3, and GLUT4 expressions when analyzing the hippocampus and cortex of 6- and 8-month-old AD mice compared to controls using immunohistochemistry and Western Blot. These results are consistent with the findings from human studies. One study did not find any AD-related differences in the hippocampal expression of these transporters when examined by Western Blot in 6-month-old mice, possibly due to the lower sensitivity of this study, combined with a lower method-related reliability [ 119 ]. Four studies examined the GLUT expression in the 5xFAD mouse model containing five different mutations linked to familial AD. This model is based on the human APP transgene with the Swedish, London, and Florida mutations and the human PSEN1 transgene with the L286V and M146L mutations. These mice develop Aβ plaques and gliosis as early as 2 months, followed by synaptic loss and cognitive impairment from 4 months of age and neuronal losses at 6 months old [ 141 ]. Ahn et al studied impaired cerebrovascular structures in 5xFAD mouse brains and found reduced GLUT1 intensities in the cortex and hippocampus in 4.5- and 9- month-old 5xFAD mice compared to wild-type controls when studied by Western Blot and immunohistochemistry [ 75 ]. On the contrary, Puris et al. did not find any significant differences in cortical GLUT1 protein expression in 7-month-old male 5xFAD mice but reported increased GLUT1 expression in 7-month-old female 5xFAD mice compared to controls when analyzing membrane fractions by LS-MS/MS [ 142 ]. Kim et al. analyzed the expression of GLUT1, GLUT2, and GLUT3 in a study investigating the effect of carboxy-dehydroevodiamine-HCl on AD-related GLUT alterations in the 5xFAD mouse model. Using Western Blot, they were able to demonstrate reduced GLUT1 and GLUT3 expressions and increased GLUT2 expression in brain homogenates from 6-month-old untreated 5xFAD mice of unreported sex compared to wild-type controls [ 143 ]. These findings were further supported by a fourth study by Nam et al., demonstrating reduced cortical GLUT3 expression in 6 to 11-month-old male 5xFAD mice by immunohistochemistry [ 97 ]. In addition, we analyzed GLUT1 gene and protein expression in 4-month-old female 5xFAD mice, compared to age-matched wild-type controls. At this age, these mice have developed both AD characteristic pathology and cognitive impairment. However, contrary to the findings in previous studies, our analysis shows a significant decrease in Glut1 gene expression in the cortex of 4-month-old 5xFAD mice (P = 0.0207), while no differences were observed in cortical protein concentrations when analyzed by ELISA (Fig. 3 ). Similar analysis of GLUT1 concentration in whole brain homogenates and hippocampal tissue from 4-month-old female 5xFAD mice also did not show any AD-related alteration of protein concentrations (data not shown). The difference between the GLUT1 gene and protein alterations found in the present study could indicate a post-transcriptional regulation of the GLUT1 expression. However, it could also be due to undetectable GLUT1 protein reductions at 4 months of age in the 5xFAD model, as the qPCR used for analysis of gene expression is generally considered a more sensitive method than the ELISA used for protein detection [ 144 ]. This interpretation agrees with the studies by Ahn et al. and Kim et al. that report a reduced GLUT1 protein expression by immunohistochemistry and Western Blot in older mice, in which GLUT1 reduction might be more prominent [ 75 , 143 ]. However, this explanation is contradicted by the results of Puris et al., demonstrating unaltered GLUT1 in 7-month-old male 5xFAD mice and increased GLUT1 in 7-month-old female mice by LC-MS/MS [ 142 ]. Taken together, it remains difficult to draw any general conclusions regarding the expression of GLUTs in the 5xFAD mouse model based on these findings due to the varying age, sex, brain regions, and methods used. GLUT alterations in mouse models based on APP, PSEN1, and MAPT mutations Five studies examined the GLUT expression in the triple transgenic mouse model 3xTg (Table 3 ), which is based on the expression of three human transgenes for both APP with the Swedish mutation, PSEN1 with a M146V mutation, and microtubule-associated protein (MAPT) with a P301L mutation linked to frontotemporal dementia [ 145 ]. These mice develop cognitive impairment at 4 months of age followed by amyloid plaques and gliosis between 6 and 7 months and extensive tau pathology at the age of 12 months [ 145 – 147 ]. Do et al., found reduced GLUT1 expression in the capillaries of 18-month-old 3xTg mice by Western Blot when compared to wild-type controls. These findings were consistent with a more recent study by Yan et al, demonstrating significantly reduced GLUT1 and GLUT3 in the cortex of 8-month-old male 3xTg mice compared to wild-type controls by Western Blot [ 148 ]. However, a study by Chen et al. revealed no significant differences in GLUT1, GLUT2, and GLUT3 in brain homogenates from 9-month-old female 3xTg mice when analyzed by Western Blot, which could indicate sex related differences in this model [ 80 ]. Li et al. analyzed the hippocampal GLUT4 expression in 11-month-old female 3xTg mice by Western Blot in a study investigating the protective effects of enhancing glucagon-like peptide 1 signaling with a dipeptidyl peptidase IV inhibitor and found a significantly reduced GLUT4 expression in 3xTg mice compared to controls[ 149 ] In summary, the results from studies performed in the triple transgenic 3xTg mouse model demonstrate reduced expression of GLUT1, 3, and 4 in cortex, capillaries, and hippocampus in male and female mice analyzed by Western Blot [ 149 – 151 ], while one study did not find any alterations of GLUT1-3 in whole brain homogenates from female mice when analyzed by Western Blot [ 80 ]. GLUT alterations in transgenic mouse models based on other mutations Four studies examined the expression of GLUTs in transgenic mouse models that are not based on APP or PSEN1 mutations (Table 3 ). Lee et al. examined the expression of GLUT1, GLUT 3, and GLUT4 in membrane proteins in 12-month-old NSE/hPS2 mice by Western Blot. These mice carry the human transgene for gamma-secretase subunit presenilin 2 (PSEN2) with the N141I mutation driven by the NSE promotor. They develop behavioral deficits by 12 months and altered Aβ42 levels, but no neuropathology has been observed [ 152 ]. Nevertheless, Lee et al. found significantly reduced GLUT1 and GLUT 3 expressions in 12-month-old NSE/hPS2 mice compared to wild-type controls, while GLUT4 expression was unchanged [ 153 ]. Zhang et al. examined the expression of GLUT1, 3, and 4 in the hippocampus of 8-month-old P301S mice, bearing the MAPT transgene with the P301S mutation, and found significantly reduced expression of all transporters when examined by Western Blot. These mice do not develop plaques, but cognitive impairment has been demonstrated from 2.5 months of age, and NFTs are detected at 4 months, while gliosis develops from 5 months [ 61 , 154 , 155 ]. Hendrix et al. examined the expression of GLUT1, GLUT2, GLUT3, and GLUT4 in a BRI-Aβ42 mouse model overexpressing human Aβ42 without an effect on APP expression, which results in plaque development and gliosis from 3 months of age [ 156 ]. Total cortical protein levels of GLUT1, GLUT3, and GLUT4 did not differ, while total GLUT2 protein was significantly reduced in BRI-Aβ42 compared to controls when analyzed by an automated capillary Western Blot assay. However, decreased astrocytic 45-kDa GLUT1 expression was noted when analyzing plasma membrane fractions, while the plasma membrane fractions of endothelial 55-kDa GLUT1, GLUT3, and GLUT4 were unchanged and undetectable for GLUT2 [ 79 ]. Finally, Janssen et al. examined hippocampal GLUT1 intensities in ApoE4 knock-in and ApoE-deficient mice in a study evaluating the effects of a high-fat diet in this model. They did, however, not find any differences in the hippocampal GLUT1 levels between ApoE4 knock-in, ApoE-deficient, and wild-type mice when examined by immunohistochemistry [ 78 ]. Overall, the results from mouse studies examining the expression of GLUTs in transgenic AD models show a tendency towards decreased GLUT1 and GLUT3 expressions, consistent with the observations in human studies. Moreover, several studies indicate a correlation between GLUT alterations and the development of AD pathologies. However, these findings are not consistent between studies or the different models investigated, which makes it difficult to draw any general conclusions regarding the expression of GLUTs in transgenic AD mouse models. Some of the variation can probably be explained by differences between the models used. However, inconsistent observations are also found within the same model, which could be due to differences in the methods used for analysis. The higher subjectivity and variability of quantitative immunohistochemistry and Western Blots, commonly used for protein quantification in most of the studies performed, could contribute to these discrepancies when compared to more precise methods for protein quantification like ELISA and LC-MS/MS [ 119 ]. GLUT alterations in non-transgenic mouse models based on aluminum chloride Two studies examined the protein expression of GLUTs in a non-transgenic AD model based on aluminum chloride administration, which has previously been linked to neurodegeneration in AD [ 157 ]. In this model, aluminum chloride administration leads to the development of oxidative stress, neuroinflammation, Aβ accumulation, and cognitive impairment [ 158 – 160 ]. Cuciniello et al. found reduced cortical GLUT1 protein levels, unchanged GLUT3, and increased GLUT4 protein levels in mice treated with 100 mg/kg added to the drinking water for 5 weeks when analyzed with Western Blot [ 161 ]. In a different study, Yang et al. found reduced GLUT1 and GLUT3 protein levels by Western Blot analysis of brain homogenates in an obesity-related AD model receiving 50 mg/kg aluminum chloride and 120mg/kg D-galactose combined with a high-fat diet for 24 weeks [ 158 ]. Both studies demonstrated AD-related pathologies simultaneously with an altered expression of GLUTs. Based on these studies, it was not possible to draw any conclusions regarding the correlation between AD pathology and the expression of GLUTs or whether one influences the other. However, while both studies demonstrate the development of neuroinflammation and neuronal damage and morphological changes, only the study by Yang et al. demonstrates Aβ accumulation, cognitive impairment, and increased concentrations of phosphorylated tau protein, characteristic of AD. Combined with the fact that Cuciniello et al. only observed a reduction in GLUT1 and not GLUT3, this could indicate that the model employed by Yang et al., which includes an extended treatment duration and combination of aluminum chloride, D-galactose, and high-fat diet, might better represent the situation in AD patients. However, this cannot be definitively concluded as it remains to be investigated whether the aluminum chloride model utilized by Cuciniello exhibits the same pathological features. Table 3 Overview of glucose transporter alterations found in mouse studies. WB: Western Blot, IHC: immunohistochemistry. *For non-transgenic models, the treatment duration in adult mice is listed instead of the animal age. Study Model Pathology Analysis GLUT alterations Name Mutations Age Sex Aβ Tau Region Method n-values GLUT1 GLUT2 GLUT3 GLUT4 Gil-Iturbe et al. 2020 Tg2576 and APPswe/PS1dE9 APP 16 months Female + - Cortex WB 4–7 Reduced Reduced Unaltered Kouznetsova et al. 2006 Tg2576 APP 18 months Unreported + - Cortex IHC 3–5 Reduced Kuznetsova et al. 2013 Tg2576 APP 4–18 months Unreported - and + - Cortex IHC 3–5 Reduced (18 months) Winkler et al. 2015 Tg2576 APP 6 months Unreported - - Cortex and hippocampus IHC 3–5 Unaltered Cho et al. 2010 NSE/APPsw APP 13 months Unreported - - Brain WB 5 Reduced Um et al. 2008 NSE/APPsw APP 13 months Unreported - - Brain WB 5 Reduced Merlini et al 2011 ArcAb mice APP 9–13 months Unreported + - Cortex and hippocampus IHC and WB Unknown Reduced Unaltered Shang et al. 2019 APP23 mice APP 12 months Male + - Cortex IHC 10–12 Reduced Hede et al. 2025* Tg-SwDI APP 24 months Mixed + - Cortex qPCR, ELISA 6 Increased Huang et al. 2024 APPswe/PS1dE9 APP, PSEN1 2, 4, and 9 months Mixed - and + - Hippocampus IHC 3 Reduced (4–9 months) Zerbi et al. 2013 APPswe/PS1dE9 APP, PSEN1 8 and 12 months Unreported - and + - Hippocampus IHC 7–9 Unaltered Hoojimans et al. 2007 APPswe/PS1dE9 APP, PSEN1 8–18 months Unreported + - Hippocampus IHC 7–10 Reduced (18 months) Khandewal et al. 2022 APPswe/PS1dE9 APP, PSEN1 8 months Male + - Brain q-PCR 7 Increased Unaltered Increased Mechlovich et al. 2014 APPswe/PS1dE9 APP, PSEN1 12 months Male + - Cortex WB 5 Reduced Ma et al. 2022 APPswe/PS1dE9 APP, PSEN1 14 months Male + - Brain WB 10 Reduced Wang et al. 2022 APPswe/PS1dE9 APP, PSEN1 2, 4, and 9 months Unreported - and + - Hippocampus IHC 5 Reduced (4–9 months) Zhang et al. 2022 APPswe/PS1dE9 APP, PSEN1 13 months Male + - Hippocampus WB 3 Unaltered Chen et al. 2018 APPswe/PS1dE9 APP, PSEN1 6 months Male + - Hippocampus WB 6 Reduced Reduced Guo et al. 2020 APPswe/PS1dE9 APP, PSEN1 6 months Male + - Cortex and hippocampus IHC 6 Reduced He et al 2022 APP/PS1 and APP/PS1- STZ ip (50 mg/kg) APP, PSEN1 6 months Male + - Hippocampus WB 3 Unaltered n.d. Unaltered Unaltered Qin et al.2021 APP/PS1 APP, PSEN1 6 months Male + - Hippocampus WB 6 Reduced Reduced Wu et al. 2019 APP/PS1 APP, PSEN1 6 months Male + - Cortex IHC and WB 12 Reduced Reduced Pang et al. 2019 APP/PS1 APP, PSEN1 8 months Male + - Cortex and hippocampus WB 5 Reduced Reduced Wang et al. 2024 APP/PS1 APP, PSEN1 3 months Male + - Cortex and hippocampus WB, qPCR 10 Reduced Reduced Reduced Qi et al. APP/PS1 APP, PSEN1 3 and 14 months Male and Female + - Hypothalamus qPCR 5 Increased (Young male, old female) Unaltered (Old male, young female) Unaltered Puris et al. 2024 5xFAD APP, PSEN1 7 months Male + Female + - Cortex LC-MS/MS 8 Unaltered Ahn et al. 2018 5xFAD APP, PSEN1 4,5 and 9 months Unreported + - Brain IHC and WB 5 (IHC) 3 (WB) Reduced Kim et al. 2022 5xFAD APP, PSEN1 6 months Unreported + - Brain WB 5–6 Reduced Increased Reduced Nam et al. 2023 5xFAD APP, PSEN1 6–11 months Male + - Cortex IHC 3 Reduced Hede et al. 2025* 5xFAD APP, PSEN1 4 months Female + - Cortex qPCR, ELISA 8 Reduced (gene), Unaltered (protein) Chen et al. 2014 3xTg mice APP, PSEN1, MAPT 9 months Female + - Brain WB 6 Unaltered Unaltered Unaltered Do et al. 2014 3xTg mice APP, PSEN1, MAPT 18 months Unreported + + Capillaries WB 4–6 Reduced Li et al. 2022 3xTg mice APP, PSEN1, MAPT 11 months Female + + Hippocampus WB 6 Reduced Yan et al. 2023 3xTg mice APP, PSEN1, MAPT 8 months Male + - Cortex WB 4–5 Reduced Reduced Hendrix et al. 2021 BRI2-Aβ42 hAβ42 over-expression 6 months Male + - Cortex SimpleWes 6 Unaltered Reduced Unaltered Unaltered Zhang et al. 2020 P301S mice MAPT 8 months Female - + Hippocampus WB 7 Reduced Reduced Reduced Lee et al. 2013 NSE/hPS2m Tg mice PSEN2 12 months Unreported - - Membrane fractions WB 3 Reduced Reduced Unaltered Janssen et al. 2016 ApoE4-knockin and knockout ApoE4 12 months Female Hippocampus IHC 6 Unaltered Cuciniello et al. 2022 AICI 3 AD model (7.7 or 100 mg/kg) - 5 weeks* Male - - Cortex WB 5 Reduced Unaltered Increased Yang et al. 2023 AICI3 (50 mg/kg), D-galactose (120 mg/kg), and high-fat diet - 24 weeks* Male (+) (+) Brain WB 3 Reduced Reduced Transgenic and non-transgenic rat models The rat studies examining GLUT expression mainly included non-transgenic models based on the administration of STZ or aluminum chloride (Table 4 ). Six studies were performed in a sporadic AD model based on single intracerebroventricular injections of 1–4 mg/kg STZ. Injecting STZ into the ventricles of rats leads to the development of cognitive impairment [ 162 , 163 ] and neuropathology similar to what is observed in sporadic AD patients, including Aβ accumulations in capillaries and neurons, leading to plaque-like formations [ 163 – 165 ] tau hyperphosphorylation and preliminary neurofibrillary tangles [ 163 , 166 , 167 ], neuroinflammation (Biasibetti et al., 2017; Kraska et al., 2012; Prickaerts et al., 1999), and neurodegeneration [ 171 ]. These studies demonstrated a decreased GLUT1 [ 166 , 171 , 172 ] and GLUT3 [ 166 , 171 – 173 ] protein expression both in the cortex and hippocampus of STZ-induced rats compared to wild-type controls when analyzed with Western Blotting. Moreover, Knezovic et al. found an increased GLUT2 protein expression in the hippocampus, but not in the cortex of STZ AD rats, compared to controls. Sajadi et al. analyzed the gene expression of GLUTs and found a decreased expression of both Glut1, Glut3 , and Glut4 in the hippocampus of STZ AD rats, consistent with the findings from studies analyzing the protein levels. Further, two studies demonstrated reduced Glut1 and Glut3 gene expression [ 174 ] and decreased hippocampal GLUT4 protein [ 175 ] in AD rat models induced by daily intraperitoneal injections of 70 mg/kg or 50 mg/kg aluminum chloride, respectively. Consistently, Radfar et al. demonstrated reduced GLUT4 gene and protein expression in the hypothalamus in an AD rat model induced by intracerebroventricular injections of 10 µg Aβ 25−35 peptide per animal [ 176 ]. Puris et al. and Ma et al. examined the GLUT1 protein expression in the cortex of transgenic TgF344 rats by LC-MS/MS and APP + PS1 rats by Western Blot, respectively [ 177 , 178 ]. Both transgenic rat models express mutated human transgenes for APP and PSEN1. TgF344 rats contain the human APP transgene with the Swedish mutation and PSEN1 lacking exon 9, similar to the APP/PS1dE9 mouse model, and develop plaques, gliosis, and cognitive impairment at 6 months of age followed by neurofibrillary tangles and neuronal loss at 15 months of age [ 179 ], while APP + PS1 rats contain human APP bearing the Swedish and Indiana mutations and PSEN1 with the L166P mutation and develop cognitive impairment and increased Aβ protein load at 10 months of age followed by Aβ plaques and neuronal loss from 18 months of age [ 177 , 180 , 181 ]. While Ma et al. found an AD-related GLUT1 reduction in 16-month-old APP + PS1 rats by Western Blot, Puris et al. found unaltered GLUT1 expression in 10-month-old TgF344 rats. At 16 months of age, the APP + PS1 model used by Ma et al. has developed cognitive impairment and increased Aβ protein load and the 10-month-old TgF344 rat model used by Puris et al. has developed Aβ plaques, gliosis, and cognitive impairment at this age. Hence, the different results in AD-related GLUT1 expressions do not correlate with differences in the development of disease pathologies between the two models used. However, Ma et al. quantified the GLUT1 protein expression by Western Blot, while Puris et al. used an LC-MS/MS-based approach to analyze the protein concentrations in the membrane fraction of cortical tissue [ 177 , 178 ]. Thus, the inconsistency could be related to the different methods used and differences between examining only the membrane fraction and all tissue components, though this should theoretically not influence the results, as GLUT1 is a transmembrane protein. Moreover, the LC-MS/MS cannot differentiate between the 55 kDa endothelial GLUT1 and the 45 kDa astrocytic GLUT1, whereas Western Blot can separate them based on size differences. Different alterations of the two GLUT1 isoforms were observed in mice by Hendrix et al., who demonstrated a reduction in astrocytic GLUT1, but unaltered membrane-associated GLUT1 in BRI2-Aβ42 mice when analyzed by Western Blot [ 79 ]. Ma et al. do not note whether the GLUT1 concentrations were quantified based on one isoform or both. Alternatively, the inconsistency could simply be related to differences between the two models, which are based on different mutations in the APP and PSEN1 genes. Nevertheless, the results from rat studies demonstrate an AD-related decrease in GLUT1 and GLUT3 expression that is more consistent across models than the observations from mouse studies, and which is similar to that found in human studies. However, the number of rat studies and variation in models used is also lower compared to the mouse studies of GLUT alteration in AD. GLUT2 expression was only analyzed in a single rat study, showing an AD-related increase, which was also consistent with the findings from the one human study examining GLUT2, while two studies consistently found reduced AD-related GLUT4 expression (Fig. 4 ). Table 4 Overview of glucose transporter alterations found in rat studies. WB: Western Blot, IHC: immunohistochemistry. *For non-transgenic models, the treatment duration in adult rats is listed instead of the animal age. Study Model Pathology Analysis GLUT alterations Name Mutations Age Sex Aβ Tau Region Method n-values GLUT1 GLUT2 GLUT3 GLUT4 Ma et al. 2024 APP + PS1 rats APP, PSEN1 16 months Female + - Cortex WB 10 Reduced Puris et al. 2022 TgF344-AD rats APP, PSEN1 10–11 months Mixed + - Cortex LC-MS/MS 6 No difference Bazzari et al. 2019 AICI3 (50 mg/kg/day i.p.) - 6 weeks* Male (+) Hippocampus WB 4 Reduced Samman et al. 2023 AICI 3 (70 mg/kg/day) - 9 weeks* Male (+) Brain qPCR 4 Reduced Reduced Radfar et al. 2024 Aβ25–35 peptide (10 µg/rat I.C.V.) - 3 weeks* Male + - Hypothalamus qPCR, ELISA 14 Reduced Deng et al. 2009 STZ icv (3 mg/kg) - 3 weeks* Male (+) (+) Brain WB 3 Reduced Reduced Knezovic et al. 2017 STZ icv (1.5 mg/kg) - 1 hour* Male (+) (+) Cortex and hippocampus WB 6 Increased (HP) Unaltered (CX) Salkovic-Petrisic et al. 2014 STZ icv (1 mg/kg) - 4 weeks* Male (+) (+) Hippocampus WB 8 Reduced Sajadi et al. 2023 STZ icv (4 mg/kg) - 3 weeks* Male (+) (+) Hippocampus qPCR 7 Reduced Reduced Reduced Biswas et al. 2018 STZ icv (3 mg/kg) - 2–3 weeks* Male (+) (+) Cortex and hippocampus WB 8–10 Reduced Reduced Pilipenko et al. 2020 STZ icv (2.7 mg/kg) - 4 weeks* Male (+) (+) Cortex and hippocampus WB 3 Reduced Reduced Discussion The findings from this systematic review and supplementary analyses of GLUT1 in Tg-SwDI and 5xFAD mice suggest that while there is nearly complete consensus in human studies that GLUT1 and GLUT3 are downregulated in AD and some evidence that GLUT2 is upregulated, the results from mouse studies, which employ a wide variety of different models and analysis methods, are far more inconsistent. In contrast, the results from rat studies, which have primarily employed fewer AD models, appear to more consistently demonstrate AD-related GLUT1 and GLUT3 reductions. Some of the variability may be explained by differences in the sex and brain regions studied and the analysis methods used, including the widespread use of methods associated with lower reliability, such as Western Blotting, and higher subjectivity, such as quantitative immunohistochemistry. However, most human studies with good concordance in their results are based on immunohistochemistry, suggesting that the difference between the results from animal studies is probably also due to the variability between the different models used and the general complexity of modelling a multifactorial disease like AD. The complexity of modelling Alzheimer’s disease Several studies indicate a correlation between the AD characteristic pathology and changes in GLUT expression. This is particularly true for Aβ plaque development, which forms the basis for most animal models, and several examples of GLUT changes have been reported after the development of Aβ plaques (Table 3 ). These findings suggest that Aβ accumulation may accelerate the GLUT alterations in AD. Moreover, Gil-Iturbe et al. analyzed the effect of direct injections of Aβ 1−42 into the brains of healthy mice, in addition to their analysis of transgene models, which resulted in reductions in GLUT1 and GLUT3 protein levels and increased GLUT12 levels similar to observations in the transgene models [ 74 ], implying that Aβ directly impacts GLUT expression. However, the study by Winkler et al. shows that GLUT1 reduction can accelerate Aβ pathology [ 70 ], potentially by affecting Aβ clearance from the brain through transcriptional inhibition of low-density lipoprotein receptor-related protein 1 (LRP1) [ 70 , 182 ]. This raises the question about what comes first in sporadic AD where the disease is not initiated by direct mutations in genes related to Aβ accumulation, as is the case in most of the animal studies included in this review. Some studies demonstrate unchanged GLUT expression in transgenic models after the development of Aβ plaques, which argues against Aβ accumulation itself initiating the GLUT changes [ 102 , 103 , 161 , 183 ]. At the same time, FDG-PET studies report reduced glucose transport long before the development of clinical AD symptoms in patients at increased risk of AD [ 54 , 55 ]. GLUT alterations observed in AD have been suggested to be linked to increased tau phosphorylation (Y. Liu et al., 2009). This could indicate that animal models with induced tauopathy would replicate this part of the AD pathology more accurately, which is supported by altered GLUT expressions in nine of the ten studies with induced tauopathy included in this review [ 149 , 150 , 158 , 166 , 171 , 172 , 183 – 186 ]. However, GLUT alterations are also prevalent in several animal models without tauopathy as shown in Tables 2 and 3 . Moreover, studies suggest that the correlation between tauopathy and altered GLUT expression can be explained through decreased levels of tau O-linked N-acetylglucosaminylation (O-GlcNAcylation), which is a distinct type of O-glycosylation within neurons that serves as a sensor of glucose metabolism and regulates intracellular protein phosphorylation [ 98 , 187 ]. The protein O-GlcNAcylation levels correlate with the levels of GLUT1 and GLUT3 proteins through positive linear correlation, indicating that the decreased GLUT1 and GLUT3 expressions in AD lead to decreased protein O-GlcNAcylation levels [ 98 ]. Additionally, O-GlcNAcylation has been shown to inversely regulate tau phosphorylation [ 188 ]. Hence, it is suggested that tau hyperphosphorylation may be caused by decreased tau O-GlcNAcylation, induced by decreased brain glucose uptake in AD [ 98 , 187 , 188 ]. Tauopathy therefore, appears to be a consequence, rather than the cause, of decreased glucose uptake resulting from decreased GLUT1 and GLUT3 expression. Several studies have proposed that alterations in brain glucose uptake may serve as an initiating factor for both Aβ accumulation and tau hyperphosphorylation in sporadic AD. This hypothesis is supported by findings from studies employing sporadic AD models, which consistently demonstrate reductions in GLUT1, GLUT3, and GLUT4 expression and an upregulation of GLUT2, which mirrors observations from human studies [ 166 , 171 – 175 , 184 , 186 ]. Additionally, this interpretation is further supported by previously described findings of reduced glucose uptake preceding the development of clinical symptoms in AD. These findings raise questions about the extent to which transgenic models based on mutations associated with familial AD adequately replicate the sporadic AD scenario, particularly concerning changes in glucose metabolism and GLUT expression. Nonetheless, alterations in GLUTs are also observed in many studies conducted in transgenic animals harboring mutations linked to familial AD. Unfortunately, due to the significant variability in pathology, age, brain regions, and methodologies employed, it is challenging to draw definitive conclusions regarding the GLUT alterations in AD animal models based on existing studies. To gain a clearer understanding of GLUT alterations in animal models, future studies should strive for better standardization of these factors. Additionally, tracer studies, such as FDG-PET, could potentially provide a more comprehensive picture of glucose metabolism changes. Tracer study results were not included in this review as they reflect glucose uptake rather than direct expression of glucose transport proteins, which was the primary focus. However, they were addressed in a previous review by Kyrtata et al., which found no significant variations in FDG-PET results across different AD animal models [ 62 ]. This observation was, however, only based on three studies. While a wide range of animal models can serve as valuable tools for investigating various aspects of AD, careful model selection becomes crucial when evaluating potential new therapies for sporadic AD. This is essential to enhance the translational value of such research and increase the likelihood of successful clinical applications [ 189 , 190 ]. Transgenic AD models offer the advantage of exploring diverse facets of the disease, allowing researchers to delve into specific genetic and molecular underpinnings. However, these models may not fully capture the complex interplay of factors that contribute to sporadic AD, which accounts for most AD cases. According to the results of the present review, the STZ rat model, on the other hand, stands out for its potential to better replicate disturbances in glucose metabolism, as evidenced by the consistent alterations in GLUT expression observed across all studies employing this model. The focus on glucose metabolism in this model also aligns with the growing recognition of its central role in AD pathogenesis. Nonetheless, the generalizability of the STZ model is challenged by the fact that it is based on the administration of a neurotoxin to induce AD pathology, which deviates from the natural development of the disease in humans. To effectively advance sporadic AD drug discovery, a balanced approach to model selection is imperative. Researchers should carefully consider the specific research question and the potential therapeutic target before choosing the most appropriate model. In addition, incorporating multiple models could be considered for future research as it can provide a more comprehensive understanding of the disease and its potential therapeutic targets and minimize the chance of making conclusions based on model-specific mechanisms, which do not correlate with the situation in AD patients. Ultimately, the goal is to identify models that strike a balance between capturing the complexity of sporadic AD and providing a robust platform for evaluating novel therapeutic strategies, which remains challenging as the etiology of sporadic AD remains unknown. However, by carefully considering the strengths and limitations of each model, the likelihood of translating preclinical findings into successful clinical applications can be increased. Correlation between alterations in brain GLUTs and insulin signaling Multiple studies have established a correlation between brain insulin resistance and altered brain BLUT expression [ 166 , 191 – 196 ]. This observation aligns with the consistent findings of GLUT dysregulation in the STZ AD models reviewed here. STZ is a glucosamine-nitrosourea compound, commonly employed to induce peripheral diabetes in animal models due to its selective toxicity toward insulin-producing cells [ 166 ]. Conversely, intracerebroventricular administration of low-dose STZ has been shown to elicit AD-like neuropathological changes rather than systemic diabetes [ 191 , 197 , 198 ]. Within the brain, insulin receptor activation triggers the phosphorylation and activation of PI3K, subsequently leading to the phosphorylation and activation of protein kinase B (Akt/PKB), which is crucial for the translocation of the insulin-dependent GLUT4 transporter to the cell membrane [ 199 ]. In addition, Akt/PKB plays an important role in regulating glucose metabolism and thereby ATP generation, insulin-degrading enzyme (IDE) activity, and glycogen synthase kinase-3 (GSK-3) phosphorylation [ 192 ]. Consequently, impaired insulin receptor signaling and reduced Akt/PKB activity contribute to diminished glucose metabolism, ATP depletion, and oxidative stress. Moreover, this may include dysregulation of IDE, due to its PI3-K-dependent regulation [ 200 ], which has been linked to the development of sporadic AD [ 201 ]. Furthermore, reduced Akt/PKB-mediated GSK-3 inhibition is associated with intracellular Aβ accumulation and tau hyperphosphorylation. Moreover, the inhibition of the PI3K pathway is responsible for regulating hypoxia-inducible factor 1, which activates the transcription of Glut1 and Glut3 [ 202 , 203 ]. When HIF-1 levels decline, GLUT1 and GLUT3 are downregulated, leading to glucose hypometabolism and reduced O-GlcNAcylation, inversely correlating with tau phosphorylation, as described above [ 98 , 187 , 188 ]. The results of this review revealed relatively few studies examining GLUT4 expression in AD and inconsistent results were reported as expression levels were shown to increase [ 131 , 161 ], decrease [ 138 , 149 , 175 , 183 , 186 ] and remain unchanged [ 74 , 77 , 79 , 153 ]. Nevertheless, alterations in GLUT expression and insulin resistance have been shown to play a role in the development of AD pathology in humans. Mullins et al. investigated the relationship between insulin resistance-related genes and AD pathologies through 3D spatial maps based on human gene expression and histological data. They found a positive correlation between GLUT4 expression and NFTs, while Glut1 gene expression correlated negatively with NFTs, indicating that regions with high GLUT4 expression and relatively low GLUT1 expression are more prone to develop tauopathy [ 204 ]. Moreover, Deng et al. demonstrated a decrease in GLUT1 and GLUT3 in the STZ rat model along with decreased insulin signaling, further emphasizing the relationship between GLUT expression and insulin signaling [ 166 ]. In addition, studies examining potential new therapies demonstrated a correlation between altered insulin signaling and the expression of GLUTs. Chen et al. investigated the mechanistic effects in transgenic APPswe/PS1dE9 mice of traditional Chinese medicine that had shown beneficial clinical effects for treating AD patients [ 127 ]. In the APPswe/PS1dE9 mouse, increased levels of PI3K, Akt, and phosphorylated Akt as well as increased GLUT1 and GLUT3 expressions were seen following the treatment, which was associated with improved cognition. Moreover, Li et al. demonstrated increased glucose uptake by FDG-PET, increased GLUT4 expression, and decreased insulin receptor inactivation leading to reduced cognitive decline in 3xTg mice following enhanced GLP1 signaling [ 149 ]. Mechlovich et al. examined the effect of an ion chelator in APPswe/PS1dE9 mice and found increased cortical insulin and insulin receptor expression, which led to increased activation of the PI3K pathway and elevated levels of HIF-1 α resulting in increased GLUT1 expression [ 132 ]. Finally, Pilipenko et al. uncovered improved cognitive performance and reduced gliosis following the normalization of glucose uptake and metabolism induced by the administration of the antidiabetic drug metformin, which increases insulin sensitivity [ 172 , 205 ]. Clinical implications of altered GLUT content in AD The critical role of GLUTs in brain function is supported by studies demonstrating substantial neurodegenerative effects following their deletion in animal models [ 70 , 206 ]. Muneer et al. demonstrated that methamphetamine-induced GLUT1 depletion in mice resulted in compromised BBB integrity, suggesting a role for GLUTs in maintaining BBB function [ 207 ]. The clinical implications of GLUT1 deficiency are evident in human GLUT1 deficiency syndrome, a rare genetic disorder characterized by impaired glucose metabolism. This condition manifests with intellectual disability, movement disorders, and refractory epilepsy [ 66 ]. Impairments in glucose metabolism precede the onset of cognitive decline in AD, as evidenced by alterations in glucose transport observed in both AD and mild cognitive impairment (MCI) (Chen and Zhong, 2013; Mosconi et al., 2013). Winkler et al. further implicated GLUT1 in AD pathogenesis, showing that GLUT1 deficiency exacerbated Aβ pathology, including reduced LRP1 expression, impaired cerebral blood flow, and accelerated BBB breakdown [ 70 ]. Moreover, several studies included in this review demonstrated improved AD symptoms and pathology along with restored GLUT expressions following various experimental treatments. Yang et al. were able to reduce Aβ aggregation and tau phosphorylation through the administration of the antioxidant polyphenol resveratrol that has known insulin signaling promoting effects, which increased the level of GLUT expression and antioxidant activity while decreasing the microglial activation in the aluminum chloride-induced sporadic AD mouse model [ 158 ]. Additionally, reduced cognitive decline and depressive behavior were observed in APP/PS1 transgenic rats following remote ischemic conditioning, which induced increased expression of GLUT1 and other BBB-related proteins along with a reduction of Aβ toxicity [ 178 ]. Sajadi et al. observed improved cognitive performance in STZ sporadic AD rats following over-expression of GLUT1, GLUT3, and GLUT4 induced by co-administration of insulin and cinnamon extract [ 186 ]. In a different study, Yan et al. demonstrated improved memory and reduced Aβ accumulation and tau phosphorylation along with increased GLUT1 and GLUT3 levels and insulin signaling following administration of icariin to 3xTg mice [ 148 ], which is the bioactive component of Chinese herbal medicine, which has shown several beneficial effects including anti-inflammatory activities, neuroprotection, and promotion of glucose metabolism [ 208 , 209 ]. Finally, Qin et al. demonstrated improvement of Aβ accumulation, neuronal degeneration, hippocampal neuron damage, and cognitive impairments along with improved glucose metabolism and transporter expression in APP/PS1 mice following administration of another traditional Chinese medicine, Shen-Zhi-Ling, which is approved by the Chinese Food and Drug Administration for treatment of mild to moderate AD [ 137 ]. Even though these findings are all pre-clinical and thereby still need to be confirmed in humans, they collectively emphasize the important role of GLUT expression in AD pathology. The expression of GLUT1 and GLUT3, and insulin-dependent GLUT4 to a minor degree, appears to play a significant role in AD development. This suggests that modulating GLUTs could be a therapeutic strategy to mitigate cognitive decline and delay AD progression. Conclusion This updated systematic review demonstrates decreased expression of GLUT1 and GLUT3 in AD patients, consistent with the findings of previous reviews [ 62 , 63 ]. This finding is replicated to some extent in rodent AD models, as 75 % of te studies examining the GLUT expression in rodent AD models also find downregulation of GLUT1 and GLUT3. However, the large variation in animal models of AD and the diversity of analytical methods may contribute to inconsistent findings, making it difficult to draw definitive conclusions. Additionally, several studies suggest a correlation between classical AD pathology and GLUT expression, but it is uncertain whether one leads to the other or vice versa, as the results from animal studies support both possibilities. Nevertheless, our findings suggest that alterations in GLUT expression may contribute to the pathogenesis of AD, highlighting the potential for targeting GLUTs as therapeutic strategies for AD. Further research is needed to elucidate the precise mechanisms underlying the GLUT changes and to explore therapeutic strategies targeting GLUTs, which could be tested in both sporadic models, such as the STZ AD model, where glucose disturbances are seemingly replicated most consistently, and transgenic models, which may more closely mimic the classical AD pathology, to increase translatability. Treatment of AD remains challenged by the fact that the precise cause of disease development remains unknown, which is likely due to the complexity of the disease. Thus, a therapeutic strategy possibly requires a combination therapy targeting multiple aspects of the pathology, including altered glucose uptake. Abbreviations AD Alzheimer's disease APP Amyloid precursor protein Aβ Amyloid-β BBB Blood-brain barrier BCEC Brain capillary endothelial cell CAA Cerebral amyloid angiopathy ELISA FDG-PET Enzyme-linked immunosorbent assay Fluorodeoxyglucose Positron Emission Tomography GLUT Glucose transporter LRP1 Lipoprotein receptor-related protein 1 MAPT Microtubule-associated protein MCI Mild cognitive impairment NFT Neurofibrillary tangles PSEN1 Presenilin 1 PSEN2 Presenilin 2 STZ Streptozotocin Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials All data generated and analyzed during this study are included in this published paper. All datasets are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was funded by Fonden til Lægevidenskabens Fremme, Lundbeck Foundation (Research Initiative on Blood–Brain Barriers and Drug Delivery Grant no. R155-2013-14113), Alzheimer-Forskningsfonden, and Svend Andersen Fonden. Authors’ contributions Conceptualization: EH, AB, TM, MST; Acquisition of data - Systematic Review: EH; Acquisition of data – Original GLUT1 Data: EH, BA, KAK, MST; Investigation: EH, MST; Writing – Original Draft: EH; Writing – Review & Editing: EH, AB, BA, KAK, TM, MST; Visualization: EH; Supervision: AB, TM, MST; Funding Acquisition: EH, TM, MST. Acknowledgements The authors thank laboratory technicians Merete Fredsgaard, Hanne Krone Nielsen, and Louise Hvilshøj Madsen, Aalborg University, Denmark, for excellent technical assistance during the study. References Oyarzabal A, Marin-Valencia I. Synaptic energy metabolism and neuronal excitability, in sickness and health. J Inherit Metab Dis [Internet]. 2019 [cited 2024 May 24];42:220–36. Available from: https://pubmed.ncbi.nlm.nih.gov/30734319/ Engl E, Attwell D. Non-signalling energy use in the brain. J Physiol [Internet]. 2015 [cited 2024 May 24];593:3417–29. Available from: https://pubmed.ncbi.nlm.nih.gov/25639777/ Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci [Internet]. 2013 [cited 2024 May 24];36:587–97. Available from: https://pubmed.ncbi.nlm.nih.gov/23968694/ Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood–brain barrier. Neurobiol Dis [Internet]. 2009 [cited 2017 Nov 15];37:13–25. Available from: https://ac-els-cdn-com.zorac.aub.aau.dk/S0969996109002083/1-s2.0-S0969996109002083-main.pdf?_tid=0f3148b4-c9fb-11e7-81cc-00000aacb35d&acdnat=1510746759_1b4a38d614c08620802aec1760f84e87 Misje Mathiisen T, Lehre KP, Christian Danbolt N, Petter Ottersen O. The Perivascular Astroglial Sheath Provides a Complete Covering of the Brain Microvessels: An Electron Microscopic 3D Reconstruction. Glia [Internet]. 2010 [cited 2017 Nov 18];58:1094–103. Available from: https://synapseweb.clm.utexas.edu/sites/default/files/synapseweb/files/2010gliamathiisenottersentheperivascastrosheath.pdf Zlokovic B V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. 2011 [cited 2023 Dec 12]; Available from: www.nature.com/reviews/neuro Zlokovic B V. The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders. Neuron [Internet]. 2008 [cited 2023 Dec 12];57:178–201. Available from: http://www.cell.com/article/S0896627308000342/fulltext Patching SG. Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery. Mol Neurobiol. 2017;54:1046–77. Simpson IA, Carruthers A, Vannucci SJ. Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters. Journal of Cerebral Blood Flow & Metabolism [Internet]. 2007 [cited 2023 Dec 12];27:1766–91. Available from: https://journals.sagepub.com/doi/10.1038/sj.jcbfm.9600521 Bouzier-Sore AK, Merle M, Magistretti PJ, Pellerin L. Feeding active neurons: (re)emergence of a nursing role for astrocytes. J Physiol Paris [Internet]. 2002 [cited 2024 May 24];96:273–82. Available from: https://pubmed.ncbi.nlm.nih.gov/12445906/ Bentsen MA, Mirzadeh Z, Schwartz MW. Revisiting how the brain senses glucose - and why. Cell Metab [Internet]. 2019 [cited 2024 May 24];29:11. Available from: /pmc/articles/PMC6326855/ Maher F, Vannucci SJ, Simpson IA. Glucose transporter proteins in brain. FASEB J [Internet]. 1994 [cited 2024 May 24];8:1003–11. Available from: https://pubmed.ncbi.nlm.nih.gov/7926364/ Gandhi GK, Cruz NF, Ball KK, Dienel GA. Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem [Internet]. 2009 [cited 2024 May 24];111:522–36. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1471-4159.2009.06333.x Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol [Internet]. 2018 [cited 2024 May 24];20:745–54. Available from: https://pubmed.ncbi.nlm.nih.gov/29950572/ Reiss AB, Gulkarov S, Jacob B, Srivastava A, Pinkhasov A, Gomolin IH, et al. Mitochondria in Alzheimer’s Disease Pathogenesis. Life 2024, Vol 14, Page 196 [Internet]. 2024 [cited 2024 May 24];14:196. Available from: https://www.mdpi.com/2075-1729/14/2/196/htm Stobart JL, Anderson CM. Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci [Internet]. 2013 [cited 2024 May 22];7. Available from: /pmc/articles/PMC3622037/ Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, et al. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease. Front Mol Neurosci [Internet]. 2016 [cited 2024 May 22];9. Available from: /pmc/articles/PMC4937039/ Henderson ST. High carbohydrate diets and Alzheimer’s disease. Med Hypotheses. 2004;62:689–700. Lin AL, Zhang W, Gao X, Watts L. Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain. Neurobiol Aging [Internet]. 2015 [cited 2024 May 24];36:2296. Available from: /pmc/articles/PMC4457572/ Takahashi S, Takahashi S. Lactate and Ketone Bodies Act as Energy Substrates as Well as Signal Molecules in the Brain. Psychology and Pathophysiological Outcomes of Eating [Internet]. 2021 [cited 2024 May 24]; Available from: https://www.intechopen.com/chapters/75814 Courchesne-Loyer A, Fortier M, Tremblay-Mercier J, Chouinard-Watkins R, Roy M, Nugent S, et al. Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: estimated potential contribution to brain energy metabolism. Nutrition [Internet]. 2013 [cited 2024 Jun 6];29:635–40. Available from: https://pubmed.ncbi.nlm.nih.gov/23274095/ Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, et al. Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition [Internet]. 2011 [cited 2024 Jun 6];27:3–20. Available from: https://pubmed.ncbi.nlm.nih.gov/21035308/ Zahoor I, Rui B, Khan J, Datta I, Giri S. An emerging potential of metabolomics in multiple sclerosis: a comprehensive overview. Cell Mol Life Sci [Internet]. 2021 [cited 2024 May 24];78:3181–203. Available from: https://pubmed.ncbi.nlm.nih.gov/33449145/ Tefera TW, Steyn FJ, Ngo ST, Borges K. CNS glucose metabolism in Amyotrophic Lateral Sclerosis: a therapeutic target? Cell & Bioscience 2021 11:1 [Internet]. 2021 [cited 2024 May 24];11:1–17. Available from: https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00511-2 Dunn L, Allen GFG, Mamais A, Ling H, Li A, Duberley KE, et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol Aging [Internet]. 2014 [cited 2024 May 24];35:1111–5. Available from: https://pubmed.ncbi.nlm.nih.gov/24300239/ Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci [Internet]. 2019 [cited 2024 May 24];20:148–60. Available from: https://pubmed.ncbi.nlm.nih.gov/30737462/ Hardy JA, Higgins GA. Alzheimer’s disease: The amyloid cascade hypothesis. Science (1979) [Internet]. 1992 [cited 2024 May 24];256:184–5. Available from: https://www.science.org/doi/10.1126/science.1566067 Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science (1979). 2003;300:486–9. Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, et al. A learning deficit related to age and β-amyloid plaques in a mouse model of alzheimer’s disease. Nature. 2000;408:975–9. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991 349:6311 [Internet]. 1991 [cited 2024 May 24];349:704–6. Available from: https://www.nature.com/articles/349704a0 Chételat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, et al. Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol [Internet]. 2010 [cited 2024 May 27];67:317–24. Available from: https://pubmed.ncbi.nlm.nih.gov/20373343/ Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A [Internet]. 1986 [cited 2024 May 27];83:4913–7. Available from: https://pubmed.ncbi.nlm.nih.gov/3088567/ Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nature Reviews Molecular Cell Biology 2007 8:2 [Internet]. 2007 [cited 2024 May 27];8:101–12. Available from: https://www.nature.com/articles/nrm2101 Eikelenboom P, Zhan SS, van Gool WA, Allsop D. Inflammatory mechanisms in Alzheimer’s disease. Trends Pharmacol Sci. 1994;15:447–50. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev. 1995;21:195–218. Rogers J, Webster S, Lue LF, Brachova L, Civin WH, Emmerling M, et al. Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging. 1996;17:681–6. Braak H, Braak E. Morphological criteria for the recognition of Alzheimer’s disease and the distribution pattern of cortical changes related to this disorder. Neurobiol Aging. 1994;15:355–6. Glenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer’s disease: Their nature and pathogenesis. Appl Pathol. 1984;2:357–69. Chow VW, Mattson MP, Wong PC, Gleichmann M. An Overview of APP Processing Enzymes and Products. Neuromolecular Med [Internet]. 2010 [cited 2024 Jul 26];12:1. Available from: /pmc/articles/PMC2889200/ Castello MA, Soriano S. On the origin of Alzheimer’s disease. Trials and tribulations of the amyloid hypothesis. Ageing Res Rev [Internet]. 2014 [cited 2024 May 27];13:10–2. Available from: https://pubmed.ncbi.nlm.nih.gov/24252390/ Morris GP, Clark IA, Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun [Internet]. 2014 [cited 2024 May 27];2. Available from: https://pubmed.ncbi.nlm.nih.gov/25231068/ Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci [Internet]. 2015 [cited 2024 May 27];18:794–9. Available from: https://pubmed.ncbi.nlm.nih.gov/26007212/ Weglinski C, Jeans A. Amyloid-β in Alzheimer’s disease — front and centre after all? Neuronal Signal [Internet]. 2023 [cited 2024 May 27];7:20220086. Available from: /neuronalsignal/article/7/1/NS20220086/232232/Amyloid-in-Alzheimer-s-disease-front-and-centre Musiek ES, Gomez-Isla T, Holtzman DM. Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside. J Clin Invest [Internet]. 2021 [cited 2024 May 27];131. Available from: https://pubmed.ncbi.nlm.nih.gov/34651585/ CH van D, CJ S, P A, RJ B, C C, M G, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med [Internet]. 2023 [cited 2024 May 27];388:142–3. Available from: https://pubmed.ncbi.nlm.nih.gov/36449413/ Budd Haeberlein S, Aisen PS, Barkhof F, Chalkias S, Chen T, Cohen S, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimers Dis [Internet]. 2022 [cited 2024 May 23];9:197–210. Available from: https://pubmed.ncbi.nlm.nih.gov/35542991/ Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature [Internet]. 2016 [cited 2024 May 23];537:50–6. Available from: https://pubmed.ncbi.nlm.nih.gov/27582220/ Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A [Internet]. 1986 [cited 2024 May 27];83:4044–8. Available from: https://pubmed.ncbi.nlm.nih.gov/2424016/ Soeda Y, Takashima A. New Insights Into Drug Discovery Targeting Tau Protein. Front Mol Neurosci. 2020;13:590896. Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study. JAMA Neurol [Internet]. 2019 [cited 2024 May 27];76:915–24. Available from: https://pubmed.ncbi.nlm.nih.gov/31157827/ 51. Landau SM, Mintun MA, Joshi AD, Koeppe RA, Petersen RC, Aisen PS, et al. Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol [Internet]. 2012 [cited 2023 Dec 12];72:578–86. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ana.23650 Chen Z, Zhong C. Oxidative stress in Alzheimer’s disease. Neurosci Bull [Internet]. 2014 [cited 2024 Jun 6];30:271–81. Available from: https://pubmed.ncbi.nlm.nih.gov/24664866/ Bhatia V, Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer’s disease. J Neurol Sci. 2021;421. Mosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, Li Y, et al. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease. Eur J Nucl Med Mol Imaging [Internet]. 2009 [cited 2023 Dec 12];36:811–22. Available from: https://link.springer.com/article/10.1007/s00259-008-1039-z Mosconi L, Rinne JO, Tsui WH, Murray J, Li Y, Glodzik L, et al. Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer’s parents. Neurobiol Aging. 2013;34:22–34. Protas HD, Chen K, Langbaum JBS, Fleisher AS, Alexander GE, Lee W, et al. Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease. JAMA Neurol [Internet]. 2013 [cited 2023 Dec 12];70:320. Available from: /pmc/articles/PMC3745014/ Ou YN, Xu W, Li JQ, Guo Y, Cui M, Chen KL, et al. FDG-PET as an independent biomarker for Alzheimer’s biological diagnosis: A longitudinal study. Alzheimers Res Ther [Internet]. 2019 [cited 2024 May 23];11:1–11. Available from: https://alzres.biomedcentral.com/articles/10.1186/s13195-019-0512-1 Bailly M, Destrieux C, Hommet C, Mondon K, Cottier JP, Beaufils E, et al. Precuneus and Cingulate Cortex Atrophy and Hypometabolism in Patients with Alzheimer’s Disease and Mild Cognitive Impairment: MRI and 18F-FDG PET Quantitative Analysis Using FreeSurfer. Biomed Res Int [Internet]. 2015 [cited 2024 May 23];2015. Available from: /pmc/articles/PMC4539420/ Zeller K, Rahner-Welsch S, Kuschinsky W. Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. Journal of Cerebral Blood Flow and Metabolism [Internet]. 1997 [cited 2023 Dec 12];17:204–9. Available from: https://journals.sagepub.com/doi/10.1097/00004647-199702000-00010?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed Choeiri C, Staines W, Miki T, Seino S, Messier C. Glucose transporter plasticity during memory processing. Neuroscience [Internet]. 2005 [cited 2023 Dec 12];130:591–600. Available from: http://www.ibroneuroscience.org/article/S030645220400836X/fulltext Allen A, Messier C. Plastic changes in the astrocyte GLUT1 glucose transporter and beta-tubulin microtubule protein following voluntary exercise in mice. Behavioural Brain Research. 2013;240:95–102. Kyrtata N, Emsley HCA, Sparasci O, Parkes LM, Dickie BR. A Systematic Review of Glucose Transport Alterations in Alzheimer’s Disease. Front Neurosci. 2021;15. Szablewski L. Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer’s Disease. Int J Mol Sci [Internet]. 2021 [cited 2024 May 21];22:8142. Available from: https://www.mdpi.com/1422-0067/22/15/8142 Szablewski L. Glucose Transporters in Brain: In Health and in Alzheimer’s Disease. Journal of Alzheimer’s Disease [Internet]. 2016 [cited 2024 May 21];55:1307–20. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JAD-160841 Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP, et al. Glut-1 deficiency syndrome: Clinical, genetic, and therapeutic aspects. Ann Neurol [Internet]. 2005 [cited 2021 Jan 20];57:111–8. Available from: http://doi.wiley.com/10.1002/ana.20331 Klepper J, Akman C, Armeno M, Auvin S, Cervenka M, Cross HJ, et al. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open [Internet]. 2020 [cited 2022 Sep 8];5:354–65. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/epi4.12414 Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, et al. Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature. 2014;509:507–11. Zhao Z, Zlokovic B V. Blood-Brain Barrier: A Dual Life of MFSD2A? Neuron [Internet]. 2014 [cited 2023 Dec 12];82:728. Available from: /pmc/articles/PMC4114515/ Zheng PP, Romme E, Van Der Spek PJ, Dirven CMF, Willemsen R, Kros JM. Glut1/SLC2A1 is crucial for the development of the blood-brain barrier in vivo. Ann Neurol [Internet]. 2010 [cited 2023 Dec 12];68:835–44. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ana.22318 Winkler EA, Nishida Y, Sagare AP, Rege S V, Bell RD, Perlmutter D, et al. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci [Internet]. 2015;18:521–30. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L602680501&from=export Niccoli T, Cabecinha M, Tillmann A, Kerr F, Wong CT, Cardenes D, et al. Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila. Current Biology [Internet]. 2016 [cited 2023 Nov 3];26:2291. Available from: /pmc/articles/PMC5026704/ Raut S, Bhalerao A, Powers M, Gonzalez M, Mancuso S, Cucullo L. Hypometabolism, Alzheimer’s Disease, and Possible Therapeutic Targets: An Overview. Cells [Internet]. 2023 [cited 2024 May 22];12. Available from: /pmc/articles/PMC10453773/ Huang X, Qi J, Su Y, Zhou Y, Wang Q, Huang T, et al. Endothelial DR6 in blood-brain barrier malfunction in Alzheimer’s disease. Cell Death Dis [Internet]. 2024;15. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2029404815&from=export Gil-Iturbe E, Solas M, Cuadrado-Tejedo M, García-Osta A, Escoté X, Ramírez MJ, et al. GLUT12 Expression in Brain of Mouse Models of Alzheimer’s Disease. Mol Neurobiol [Internet]. 2020 [cited 2024 May 21];57:798–805. Available from: https://link.springer.com/10.1007/s12035-019-01743-1 Ahn K-C, Learman CR, Dunbar GL, Maiti P, Jang W-C, Cha H-C, et al. Characterization of Impaired Cerebrovascular Structure in APP/PS1 Mouse Brains. Neuroscience [Internet]. 2018;385:246–54. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2000796072&from=export Kuznetsova E, Schliebs R. βAmyloid, cholinergic transmission, and cerebrovascular system - a developmental study in a mouse model of alzheimer’s disease. Curr Pharm Des [Internet]. 2013;19:6749–65. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L605249728&from=export He C, Li Q, Cui Y, Gao P, Shu W, Zhou Q, et al. Recurrent moderate hypoglycemia accelerates the progression of Alzheimer’s disease through impairment of the TRPC6/GLUT3 pathway. JCI Insight [Internet]. 2022 [cited 2024 May 21];7. Available from: https://insight.jci.org/articles/view/154595 Janssen CIF, Jansen D, Mutsaers MPC, Dederen PJWC, Geenen B, Mulder MT, et al. The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice. Schulz C, editor. PLoS One [Internet]. 2016 [cited 2024 May 21];11:e0155307. Available from: https://dx.plos.org/10.1371/journal.pone.0155307 Hendrix RD, Ou Y, Davis JE, Odle AK, Groves TR, Allen AR, et al. Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood. Neurobiol Aging [Internet]. 2021 [cited 2024 May 21];97:73–88. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0197458020303109 Chen Y, Zhao Y, Dai C-L, Liang Z, Run X, Iqbal K, et al. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Aβ level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol [Internet]. 2014;261:610–9. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L373855009&from=export Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 [cited 2024 Jun 8];372. Available from: https://www.bmj.com/content/372/bmj.n71 Livak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2 C T Method. METHODS. 2001;25:402–8. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. Journal of Neuroscience [Internet]. 2014 [cited 2024 Jul 18];34:11929–47. Available from: https://www.jneurosci.org/content/34/36/11929 Burgos M, Gil-Iturbe E, Idoate-Bayón A, Castilla-Madrigal R, Moreno-Aliaga MJ, Lostao MP. The glucose transporter GLUT12, a new actor in obesity and cancer. J Physiol Biochem [Internet]. 2024 [cited 2024 Jul 19];1–11. Available from: https://link.springer.com/article/10.1007/s13105-024-01028-9 Burke MJC, Nelson L, Slade JY, Oakley AE, Khundakar AA, Kalaria RN. Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias. Neuropathol Appl Neurobiol [Internet]. 2014;40:284–95. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L372595495&from=export Kalaria RN, Harik SI. Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J Neurochem [Internet]. 1989;53:1083–8. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L19238473&from=export Horwood N, Davies DC. Immunolabelling of hippocampal microvessel glucose transporter protein is reduced in Alzheimer’s disease. Virchows Archiv [Internet]. 1994;425:69–72. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L24295508&from=export Kawai M, Kalaria RN, Harik SI, Perry G. The relationship of amyloid plaques to cerebral capillaries in Alzheimer’s disease. American Journal of Pathology [Internet]. 1990;137:1435–46. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L21046307&from=export Simpson IA, Davies P. Reduced glucose transporter concentrations in brains of patients with Alzheimer’s disease. Ann Neurol [Internet]. 1994 [cited 2024 May 21];36:800–1. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ana.410360522 Harr SD, Simonian NA, Hyman BT. Functional alterations in Alzheimer’s disease: Decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J Neuropathol Exp Neurol [Internet]. 1995;54:38–41. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L25018569&from=export An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimer’s & Dementia [Internet]. 2018 [cited 2024 May 21];14:318–29. Available from: https://alz-journals.onlinelibrary.wiley.com/doi/10.1016/j.jalz.2017.09.011 Wang Q, Huang X, Su Y, Yin G, Wang S, Yu B, et al. Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease. Brain [Internet]. 2022 [cited 2024 May 21];145:4474–88. Available from: https://academic.oup.com/brain/article/145/12/4474/6630034 Leclerc M, Tremblay C, Bourassa P, Schneider JA, Bennett DA, Calon F. Lower GLUT1 and unchanged MCT1 in Alzheimer’s disease cerebrovasculature. Journal of Cerebral Blood Flow and Metabolism. 2024; Mooradian AD, Chung HC, Shah GN. GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging [Internet]. 1997;18:469–74. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L27497142&from=export Jin N, Qian W, Yin X, Zhang L, Iqbal K, Grundke-Iqbal I, et al. CREB regulates the expression of neuronal glucose transporter 3: A possible mechanism related to impaired brain glucose uptake in Alzheimer’s disease. Nucleic Acids Res [Internet]. 2013;41:3240–56. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L368759985&from=export Liu Y, Liu F, Grundke‐Iqbal I, Iqbal K, Gong C. Brain glucose transporters, O ‐GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer’s disease. J Neurochem [Internet]. 2009 [cited 2024 May 21];111:242–9. Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.06320.x Nam M-H, Ko HY, Kim D, Lee S, Park YM, Hyeon SJ, et al. Visualizing reactive astrocyte-neuron interaction in Alzheimer’s disease using 11C-acetate and 18F-FDG. Brain [Internet]. 2023 [cited 2024 May 21];146:2957–74. Available from: https://academic.oup.com/brain/article/146/7/2957/7117615 98. Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong C-X. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett [Internet]. 2008;582:359–64. Available from: https://febs.onlinelibrary.wiley.com/doi/10.1016/j.febslet.2007.12.035 Kouznetsova E, Klingner M, Sorger D, Sabri O, Großmann U, Steinbach J, et al. Developmental and amyloid plaque‐related changes in cerebral cortical capillaries in transgenic Tg2576 Alzheimer mice. International Journal of Developmental Neuroscience [Internet]. 2006 [cited 2024 May 21];24:187–93. Available from: https://onlinelibrary.wiley.com/doi/10.1016/j.ijdevneu.2005.11.011 Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science [Internet]. 1996 [cited 2024 Jun 17];274:99–102. Available from: https://pubmed.ncbi.nlm.nih.gov/8810256/ Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol [Internet]. 1998 [cited 2024 Jul 19];152:307. Available from: /pmc/articles/PMC1858113/?report=abstract Um HS, Kang EB, Leem YH, Cho IH, Yang CH, Chae KR, et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phonetypes for Alzheimer’s disease in an NSE/APPSw-transgenic model. Int J Mol Med [Internet]. 2008 [cited 2024 May 21];22:529–39. Available from: http://www.spandidos-publications.com/10.3892/ijmm_00000052/abstract Cho JY, Um HS, Kang EB, Cho IH, Kim CH, Cho JS, et al. The combination of exercise training and α-lipoic acid treatment has therapeutic effects on the pathogenic phenotypes of Alzheimer’s disease in NSE/APPsw-transgenic mice. Int J Mol Med [Internet]. 2010;25:337–46. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L358316176&from=export Hwang DY, Cho JS, Lee SH, Chae KR, Lim HJ, Min SH, et al. Aberrant expressions of pathogenic phenotype in Alzheimer’s diseased transgenic mice carrying NSE-controlled APPsw. Exp Neurol [Internet]. 2004 [cited 2024 Jun 25];186:20–32. Available from: https://pubmed.ncbi.nlm.nih.gov/14980807/ Kim JH, Nam YP, Jeon SM, Han HS, Suk K. Amyloid neurotoxicity is attenuated by metallothionein: dual mechanisms at work. J Neurochem [Internet]. 2012 [cited 2024 Jun 25];121:751–62. Available from: https://pubmed.ncbi.nlm.nih.gov/22404335/ Shang J, Yamashita T, Tian F, Li X, Liu X, Shi X, et al. Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse. Brain Res [Internet]. 2019;1723. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2002702172&from=export Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A [Internet]. 1997 [cited 2024 Jun 25];94:13287–92. Available from: https://pubmed.ncbi.nlm.nih.gov/9371838/ Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, et al. Neuron loss in APP transgenic mice. Nature [Internet]. 1998 [cited 2024 Jun 25];395:755–6. Available from: https://pubmed.ncbi.nlm.nih.gov/9796810/ Kelly PH, Bondolfi L, Hunziker D, Schlecht HP, Carver K, Maguire E, et al. Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol Aging [Internet]. 2003 [cited 2024 Jun 25];24:365–78. Available from: https://pubmed.ncbi.nlm.nih.gov/12498971/ Reichwald J, Danner S, Wiederhold KH, Staufenbiel M. Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation [Internet]. 2009 [cited 2024 Jul 19];6:1–12. Available from: https://link.springer.com/articles/10.1186/1742-2094-6-35 Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice. Acta Neuropathol [Internet]. 2011 [cited 2024 May 21];122:293–311. Available from: http://link.springer.com/10.1007/s00401-011-0834-y Knobloch M, Konietzko U, Krebs DC, Nitsch RM. Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging [Internet]. 2007 [cited 2024 Jun 25];28:1297–306. Available from: https://pubmed.ncbi.nlm.nih.gov/16876915/ Miao J, Xu F, Davis J, Otte-Höller I, Verbeek MM, Van Nostrand WE. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol [Internet]. 2005 [cited 2024 Jun 25];167:505–15. Available from: https://pubmed.ncbi.nlm.nih.gov/16049335/ Davis J, Xu F, Deane R, Romanov G, Previti M Lou, Zeigler K, et al. Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor. Journal of Biological Chemistry. 2004;279:20296–306. Spina S, La Joie R, Petersen C, Nolan AL, Cuevas D, Cosme C, et al. Comorbid neuropathological diagnoses in early versus late-onset Alzheimer’s disease. Brain [Internet]. 2021 [cited 2024 Jul 19];144:2186–98. Available from: https://dx.doi.org/10.1093/brain/awab099 Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain [Internet]. 2013 [cited 2024 Jul 19];136:2697–706. Available from: https://dx.doi.org/10.1093/brain/awt188 Xu F, Grande AM, Robinson JK, Previti ML, Vasek M, Davis J, et al. Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid β-protein precursor transgenic mice. Neuroscience. 2007;146:98–107. Wang L, Pavlou S, Du X, Bhuckory M, Xu H, Chen M. Glucose transporter 1 critically controls microglial activation through facilitating glycolysis. Mol Neurodegener [Internet]. 2019 [cited 2025 May 12];14. Available from: https://doi.org/10.1186/s13024-019-0305-9 Oh S hee, Choi Y bok, Kim J hyun, Weihl CC, Ju J sun. Comparisons of ELISA and Western blot assays for detection of autophagy flux. Data Brief [Internet]. 2017 [cited 2024 Jul 19];13:696. Available from: /pmc/articles/PMC5506881/ Jensen K, Krusenstjerna-Hafstrøm R, Lohse J, Petersen KH, Derand H. A novel quantitative immunohistochemistry method for precise protein measurements directly in formalin-fixed, paraffin-embedded specimens: analytical performance measuring HER2. Modern Pathology [Internet]. 2017 [cited 2024 Jul 26];30:180–93. Available from: http://www.modernpathology.org/article/S089339522201273X/fulltext Gil-Iturbe E, Solas M, Cuadrado-Tejedo M, Ramírez MJ, Lostao MP. Expression of the glucose transporter GLUT12 in mouse models of Alzheimer’s disease and aging. Acta Physiologica [Internet]. 2019;227:83–4. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L631555151&from=export Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet [Internet]. 2004 [cited 2024 Jun 25];13:159–70. Available from: https://pubmed.ncbi.nlm.nih.gov/14645205/ Volianskis A, Køstner R, Mølgaard M, Hass S, Jensen MS. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1δE9-deleted transgenic mice model of ß-amyloidosis. Neurobiol Aging [Internet]. 2010 [cited 2024 Jun 25];31:1173–87. Available from: https://pubmed.ncbi.nlm.nih.gov/18790549/ Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AHP, et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One [Internet]. 2012 [cited 2024 Jun 25];7. Available from: https://pubmed.ncbi.nlm.nih.gov/22912745/ Ma H-H, Wan C, Zhang L-D, Zhang R-R, Peng D, Qiao L-J, et al. Sodium tanshinone IIA sulfonate improves cognitive impairment via regulating Aβ transportation in AD transgenic mouse model. Metab Brain Dis [Internet]. 2022 [cited 2024 May 21];37:989–1001. Available from: https://link.springer.com/10.1007/s11011-022-00911-y Hooijmans CR, Graven C, Dederen PJ, Tanila H, van Groen T, Kiliaan AJ. Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice. Brain Res [Internet]. 2007;1181:93–103. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L350050914&from=export Chen F, He Y, Wang P, Wei P, Feng H, Rao Y, et al. Banxia Xiexin decoction ameliorated cognition via the regulation of insulin pathways and glucose transporters in the hippocampus of APPswe/PS1dE9 mice. Int J Immunopathol Pharmacol [Internet]. 2018 [cited 2024 May 21];32:205873841878006. Available from: http://journals.sagepub.com/doi/10.1177/2058738418780066 Guo Y, Ma X, Li P, Dong S, Huang X, Ren X, et al. High-fat diet induced discrepant peripheral and central nervous systems insulin resistance in APPswe/PS1dE9 and wild-type C57BL/6J mice. Aging [Internet]. 2020;13:1236–50. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L633663817&from=export Zerbi V, Jansen D, Dederen PJ, Veltien A, Hamans B, Liu Y, et al. Microvascular cerebral blood volume changes in aging APPswe/PS1dE9 AD mouse model: a voxel-wise approach. Brain Struct Funct [Internet]. 2013 [cited 2024 May 21];218:1085–98. Available from: http://link.springer.com/10.1007/s00429-012-0448-8 Zhang S, Zhu L, Peng Y, Zhang L, Chao F, Jiang L, et al. Long-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice. J Neuroinflammation [Internet]. 2022 [cited 2024 May 21];19:34. Available from: https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-022-02401-5 Khandelwal M, Manglani K, Upadhyay P, Azad M, Gupta S. AdipoRon induces AMPK activation and ameliorates Alzheimer’s like pathologies and associated cognitive impairment in APP/PS1 mice. Neurobiol Dis [Internet]. 2022 [cited 2024 May 21];174:105876. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0969996122002686 Mechlovich D, Amit T, Bar-Am O, Mandel S, Youdim MBH, Weinreb O. The novel multi-target iron chelator, M30 modulates HIF-1α-related glycolytic genes and insulin signaling pathway in the frontal cortex of APP/PS1 Alzheimer’s disease mice. Curr Alzheimer Res [Internet]. 2014;11:119–27. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L372738595&from=export Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep [Internet]. 2006 [cited 2024 Jun 25];7:940–6. Available from: https://pubmed.ncbi.nlm.nih.gov/16906128/ Rupp NJ, Wegenast-Braun BM, Radde R, Calhoun ME, Jucker M. Early onset amyloid lesions lead to severe neuritic abnormalities and local, but not global neuron loss in APPPS1 transgenic mice. Neurobiol Aging [Internet]. 2011 [cited 2024 Jun 25];32:2324.e1-2324.e6. Available from: https://pubmed.ncbi.nlm.nih.gov/20970889/ Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horré K, Van Houtvin T, et al. gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer’s disease. Science [Internet]. 2009 [cited 2024 Jun 25];324:639–42. Available from: https://pubmed.ncbi.nlm.nih.gov/19299585/ Pang R, Wang X, Pei F, Zhang W, Shen J, Gao X, et al. Regular Exercise Enhances Cognitive Function and Intracephalic GLUT Expression in Alzheimer’s Disease Model Mice. Journal of Alzheimer’s Disease [Internet]. 2019 [cited 2024 May 21];72:83–96. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JAD-190328 Qin G, Dong Y, Liu Z, Gong Z, Gao C, Zheng M, et al. Shen-Zhi-Ling oral liquid ameliorates cerebral glucose metabolism disorder in early AD via insulin signal transduction pathway in vivo and in vitro. Chinese Medicine (United Kingdom) [Internet]. 2021;16. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2014344048&from=export Wu H, Wu Z, Shi W, Gao H, Wu H, Bian F, et al. Effects of progesterone on glucose uptake in neurons of Alzheimer’s disease animals and cell models. Life Sci [Internet]. 2019 [cited 2024 May 21];238:116979. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0024320519309063 Wang Y, Ruan Y, Cui C, Wang X. Jiaotaiwan improves brain glucose metabolism in a mouse model of Alzheimer’s disease by activating the PI3K/AKT signaling pathway. Nan Fang Yi Ke Da Xue Xue Bao [Internet]. 2024;44:894–903. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L644504418&from=export Qi G, Tang H, Gong P, Liu Y, He C, Hu J, et al. Sex-specific hypothalamic neuropathology and glucose metabolism in an amyloidosis transgenic mouse model of Alzheimer’s disease. Cell Biosci. 2024;14. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci [Internet]. 2006 [cited 2024 Jun 25];26:10129–40. Available from: https://pubmed.ncbi.nlm.nih.gov/17021169/ Puris E, Saveleva L, Auriola S, Gynther M, Kanninen KM, Fricker G. Sex-specific changes in protein expression of membrane transporters in the brain cortex of 5xFAD mouse model of Alzheimer’s disease. Front Pharmacol [Internet]. 2024;15. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2029281634&from=export Kim J, Kang S, Chang K-A. Effect of cx-DHED on Abnormal Glucose Transporter Expression Induced by AD Pathologies in the 5xFAD Mouse Model. Int J Mol Sci [Internet]. 2022 [cited 2024 May 21];23:10602. Available from: https://www.mdpi.com/1422-0067/23/18/10602 Nyirenda JT, Henrion MYR, Nyasulu V, Msakwiza M, Nedi W, Thole H, et al. Examination of ELISA against PCR for assessing treatment efficacy against Cryptosporidium in a clinical trial context. PLoS One [Internet]. 2023 [cited 2024 Jul 26];18. Available from: /pmc/articles/PMC10490871/ Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s Disease with plaques and tangles: Intracellular Aβ and synaptic dysfunction. Neuron [Internet]. 2003 [cited 2024 Jun 25];39:409–21. Available from: https://pubmed.ncbi.nlm.nih.gov/12895417/ Caruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike CJ, et al. Age-related changes in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging [Internet]. 2013 [cited 2024 Jun 25];34:1080. Available from: /pmc/articles/PMC3545103/ Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron [Internet]. 2005 [cited 2024 Jun 25];45:675–88. Available from: https://pubmed.ncbi.nlm.nih.gov/15748844/ Yan D, Qu X, Chen M, Wang J, Li X, Zhang Z, et al. Functionalized curcumin/ginsenoside Rb1 dual-loaded liposomes: Targeting the blood-brain barrier and improving pathological features associated in APP/PS-1 mice. J Drug Deliv Sci Technol [Internet]. 2023;86. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2025130168&from=export Li Z, Zhang Y, Meng X, Li M, Cao W, Yang J, et al. A novel DPP-4 inhibitor Gramcyclin A attenuates cognitive deficits in APP/PS1/tau triple transgenic mice via enhancing brain GLP-1-dependent glucose uptake. Phytotherapy Research [Internet]. 2022;36:1297–309. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2014864426&from=export Do TM, Alata W, Dodacki A, Traversy M-T, Chacun H, Pradier L, et al. Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer’s disease. Neuropharmacology [Internet]. 2014;81:311–7. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L372677562&from=export Yan F, Liu J, Chen M-X, Zhang Y, Wei S-J, Jin H, et al. Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice. Neural Regen Res [Internet]. 2023;18:183–8. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L639663625&from=export Hwang DY, Chae KR, Kang TS, Hwang JH, Lim CH, Kang HK, et al. Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer’s disease. FASEB J [Internet]. 2002 [cited 2024 Jun 25];16:805–13. Available from: https://pubmed.ncbi.nlm.nih.gov/12039862/ Lee YJ, Kim JE, Hwang IS, Kwak MH, Lee JH, Jung YJ, et al. Alzheimer’s phenotypes induced by overexpression of human presenilin 2 mutant proteins stimulate significant changes in key factors of glucose metabolism. Mol Med Rep [Internet]. 2013;7:1571–8. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L368691964&from=export Hampton DW, Webber DJ, Bilican B, Goedert M, Spillantini MG, Chandran S. Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy. The Journal of Neuroscience [Internet]. 2010 [cited 2024 Jun 25];30:9973. Available from: /pmc/articles/PMC6633376/ Xu H, Rösler TW, Carlsson T, de Andrade A, Bruch J, Höllerhage M, et al. Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice. Neuropathol Appl Neurobiol [Internet]. 2014 [cited 2024 Jun 25];40:833–43. Available from: https://pubmed.ncbi.nlm.nih.gov/24865638/ McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, et al. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron [Internet]. 2005 [cited 2024 Jun 25];47:191–9. Available from: https://pubmed.ncbi.nlm.nih.gov/16039562/ Dey M, Singh RK. Neurotoxic effects of aluminium exposure as a potential risk factor for Alzheimer’s disease. Pharmacol Rep [Internet]. 2022 [cited 2024 Jun 19];74:439–50. Available from: https://pubmed.ncbi.nlm.nih.gov/35088386/ Yang L, Wang Y, Li Z, Wu X, Mei J, Zheng G. Brain targeted peptide-functionalized chitosan nanoparticles for resveratrol delivery: Impact on insulin resistance and gut microbiota in obesity-related Alzheimer’s disease. Carbohydr Polym [Internet]. 2023 [cited 2024 May 21];310:120714. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0144861723001789 Abu-Taweel GM, Al-Mutary MG. Pomegranate juice reverses AlCl3-Induced neurotoxicity and improves learning and memory in female mice. Environ Res [Internet]. 2021;199:111270. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0013935121005648 Kumar R, Kumar R, Sharma N, Khurana N, Singh SK, Satija S, et al. Pharmacological evaluation of bromelain in mouse model of Alzheimer’s disease. Neurotoxicology [Internet]. 2022 [cited 2024 Jul 1];90:19–34. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0161813X22000286 Cuciniello R, Luongo D, Ferramosca A, Lunetti P, Rotondi-Aufiero V, Crispi S, et al. Conjugated linoleic acid downregulates Alzheimer’s hallmarks in aluminum mouse model through an Nrf2-mediated adaptive response and increases brain glucose transporter levels. Free Radic Biol Med [Internet]. 2022 [cited 2024 May 21];191:48–58. Available from: https://linkinghub.elsevier.com/retrieve/pii/S089158492200555X Mayer G, Nitsch R, Hoyer S. Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res. 1990;532:95–100. Knezovic A, Osmanovic-Barilar J, Curlin M, Hof PR, Simic G, Riederer P, et al. Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease. J Neural Transm [Internet]. 2015 [cited 2024 Jun 26];122:577–92. Available from: https://link.springer.com/article/10.1007/s00702-015-1394-4 Salkovic-Petrisic M, Tribl F, Schmidt M, Hoyer S, Riederer P. Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem [Internet]. 2006;96:1005–15. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L43433021&from=export Salkovic-Petrisic M, Osmanovic-Barilar J, Brückner MK, Hoyer S, Arendt T, Riederer P. Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: A long-term follow up study. J Neural Transm [Internet]. 2011 [cited 2024 Jun 26];118:765–72. Available from: https://link.springer.com/article/10.1007/s00702-011-0651-4 Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong C-X. Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: Implication for Alzheimer’s disease. American Journal of Pathology [Internet]. 2009;175:2089–98. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L358071935&from=export Osmanovic Barilar J, Knezovic A, Grünblatt E, Riederer P, Salkovic-Petrisic M. Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer’s disease. J Neural Transm [Internet]. 2015 [cited 2024 Jun 26];122:565–76. Available from: https://link.springer.com/article/10.1007/s00702-014-1323-y Prickaerts J, Fahrig T, Blokland A. Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis. Behavioural Brain Research. 1999;102:73–88. Kraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, et al. In Vivo Cross-sectional Characterization of Cerebral Alterations Induced by Intracerebroventricular Administration of Streptozotocin. PLoS One [Internet]. 2012 [cited 2024 Jun 26];7:e46196. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046196 Biasibetti R, Almeida dos Santos JP, Rodrigues L, Wartchow KM, Suardi LZ, Nardin P, et al. Hippocampal changes in STZ-model of Alzheimer’s disease are dependent on sex. Behavioural Brain Research. 2017;316:205–14. Biswas J, Gupta S, Verma DK, Gupta P, Singh A, Tiwari S, et al. Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer’s like pathology. Cell Signal [Internet]. 2018;42:211–26. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L619123497&from=export Pilipenko V, Narbute K, Pupure J, Langrate IK, Muceniece R, Kluša V. Neuroprotective potential of antihyperglycemic drug metformin in streptozocin-induced rat model of sporadic Alzheimer’s disease. Eur J Pharmacol [Internet]. 2020 [cited 2024 May 21];881:173290. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014299920303824 Salkovic-Petrisic M, Knezovic A, Osmanovic-Barilar J, Reutter W. Therapeutic effect of oral galactose treatment in a rat model of sporadic Alzheimer’s disease. Alzheimer’s and Dementia [Internet]. 2014;10:P464. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L71627944&from=export Samman WA, Selim SM, El Fayoumi HM, El-Sayed NM, Mehanna ET, Hazem RM. Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer’s Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism. Pharmaceuticals [Internet]. 2023;16. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2023427699&from=export Bazzari FH, Abdallah DM, El-Abhar HS. Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats. Molecules [Internet]. 2019;24. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L628137151&from=export Radfar F, Shahbazi M, Tahmasebi Boroujeni S, Arab Ameri E, Farahmandfar M. Moderate aerobic training enhances the effectiveness of insulin therapy through hypothalamic IGF1 signaling in rat model of Alzheimer’s disease. Sci Rep [Internet]. 2024 [cited 2025 Jul 1];14:15996. Available from: https://www.nature.com/articles/s41598-024-66637-2 Puris E, Auriola S, Petralla S, Hartman R, Gynther M, de Lange ECM, et al. Altered protein expression of membrane transporters in isolated cerebral microvessels and brain cortex of a rat Alzheimer’s disease model. Neurobiol Dis. 2022;169:105741. Ma Y, Sun W, Bai J, Gao F, Ma H, Liu H, et al. Targeting blood brain barrier—Remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats. CNS Neurosci Ther [Internet]. 2024;30. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2028621920&from=export Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci [Internet]. 2013 [cited 2024 Jun 26];33:6245–56. Available from: https://pubmed.ncbi.nlm.nih.gov/23575824/ Klakotskaia D, Agca C, Richardson RA, Stopa EG, Schachtman TR, Agca Y. Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer’s disease. PLoS One [Internet]. 2018 [cited 2024 Jun 26];13. Available from: https://pubmed.ncbi.nlm.nih.gov/29641600/ Agca C, Klakotskaia D, Schachtman TR, Chan AW, Lah JJ, Agca Y. Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention. BMC Neurosci [Internet]. 2016 [cited 2024 Jun 26];17. Available from: https://pubmed.ncbi.nlm.nih.gov/27388605/ Kanekiyo T, Cirrito JR, Liu CC, Shinohara M, Li J, Schuler DR, et al. Neuronal clearance of amyloid-β by endocytic receptor LRP1. J Neurosci [Internet]. 2013 [cited 2024 Jul 26];33:19276–83. Available from: https://pubmed.ncbi.nlm.nih.gov/24305823/ Zhang Y-H, Yan X-Z, Xu S-F, Pang Z-Q, Li L-B, Yang Y, et al. α-Lipoic Acid Maintains Brain Glucose Metabolism via BDNF/TrkB/HIF-1α Signaling Pathway in P301S Mice. Front Aging Neurosci [Internet]. 2020;12. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L632736565&from=export Knezovic A, Loncar A, Homolak J, Smailovic U, Osmanovic Barilar J, Ganoci L, et al. Rat brain glucose transporter-2, insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer’s disease? J Neural Transm [Internet]. 2017;124:695–708. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L615890534&from=export Salkovic-Petrisic M, Osmanovic-Barilar J, Knezovic A, Hoyer S, Mosetter K, Reutter W. Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin. Neuropharmacology [Internet]. 2014;77:68–80. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L370075184&from=export Sajadi E, Sajedianfard J, Hosseinzadeh S, Taherianfard M. Effect of insulin and cinnamon extract on spatial memory and gene expression of GLUT1, 3, and 4 in streptozotocin-induced Alzheimer’s model in rats. Iran J Basic Med Sci [Internet]. 2023;26:680–7. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2025285910&from=export Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis [Internet]. 2006 [cited 2024 Jul 25];9:1–12. Available from: https://pubmed.ncbi.nlm.nih.gov/16627930/ Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci U S A [Internet]. 2004 [cited 2024 Jul 25];101:10804. Available from: /pmc/articles/PMC490015/ Vitek MP, Araujo JA, Fosse M, Greenberg BD, Howell GR, Rizzo SJS, et al. Translational animal models for Alzheimer’s disease: An Alzheimer’s Association Business Consortium Think Tank. Alzheimer’s & Dementia : Translational Research & Clinical Interventions [Internet]. 2020 [cited 2024 Jul 26];6. Available from: /pmc/articles/PMC7798310/ Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther [Internet]. 2014 [cited 2024 Jul 26];6:37. Available from: /pmc/articles/PMC4095696/ Grünblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S. Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem [Internet]. 2007;101:757–70. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L46633313&from=export Salkovic-Petrisic M, Osmanovic J, Grünblatt E, Riederer P, Hoyer S. Modeling Sporadic Alzheimer’s Disease: The Insulin Resistant Brain State Generates Multiple Long-Term Morphobiological Abnormalities Including Hyperphosphorylated Tau Protein and Amyloid-β. Journal of Alzheimer’s Disease [Internet]. 2009;18:729–50. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JAD-2009-1184 Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol [Internet]. 2006 [cited 2024 Jul 26];199:265–73. Available from: https://pubmed.ncbi.nlm.nih.gov/16515786/ Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging [Internet]. 2006 [cited 2024 Jul 26];27:451–8. Available from: https://pubmed.ncbi.nlm.nih.gov/15964100/ Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis [Internet]. 2008 [cited 2024 Jul 26];13:323–31. Available from: https://pubmed.ncbi.nlm.nih.gov/18430999/ Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry [Internet]. 2005 [cited 2024 Jul 26];13:950–8. Available from: https://pubmed.ncbi.nlm.nih.gov/16286438/ Salkovic-Petrisic M, Hoyer S. Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl [Internet]. 2007 [cited 2024 Jul 26];217–33. Available from: https://pubmed.ncbi.nlm.nih.gov/17982898/ Correia SC, Santos RX, Perry G, Zhu X, IMoreira PI, Smith MA. Insulin-Resistant Brain State: the culprit in sporadic Alzheimer’s Disease? Ageing Res Rev [Internet]. 2011 [cited 2024 Jul 26];10:264. Available from: /pmc/articles/PMC3056939/ Benomar Y, Naour N, Aubourg A, Bailleux V, Gertler A, Djiane J, et al. Insulin and Leptin Induce Glut4 Plasma Membrane Translocation and Glucose Uptake in a Human Neuronal Cell Line by a Phosphatidylinositol 3-Kinase- Dependent Mechanism. Endocrinology [Internet]. 2006 [cited 2024 Jul 25];147:2550–6. Available from: https://dx.doi.org/10.1210/en.2005-1464 Zhao L, Teter B, Morihara T, Lim GP, Ambegaokar SS, Ubeda OJ, et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer’s disease intervention. J Neurosci [Internet]. 2004 [cited 2024 Jul 25];24:11120–6. Available from: https://pubmed.ncbi.nlm.nih.gov/15590928/ Ertekin-Taner N, Allen M, Fadale D, Scanlin L, Younkin L, Petersen RC, et al. Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat [Internet]. 2004 [cited 2024 Jul 25];23:334–42. Available from: https://pubmed.ncbi.nlm.nih.gov/15024728/ Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J [Internet]. 1998 [cited 2024 Jul 25];17:5085–94. Available from: https://pubmed.ncbi.nlm.nih.gov/9724644/ Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem [Internet]. 2001 [cited 2024 Jul 25];276:9519–25. Available from: https://pubmed.ncbi.nlm.nih.gov/11120745/ Mullins RJ, Diehl TC, Chia CW, Kapogiannis D. Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease. Front Aging Neurosci [Internet]. 2017 [cited 2024 May 21];9. Available from: http://journal.frontiersin.org/article/10.3389/fnagi.2017.00118/full Pernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol [Internet]. 2014 [cited 2024 Jul 26];10:143–56. Available from: https://pubmed.ncbi.nlm.nih.gov/24393785/ Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer’s mouse brain: Implication for bioenergetic intervention. PLoS One [Internet]. 2013;8. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L372232393&from=export Abdul Muneer PM, Alikunju S, Szlachetka AM, Murrin LC, Haorah J. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction. Mol Neurodegener [Internet]. 2011 [cited 2024 Jul 26];6:23. Available from: /pmc/articles/PMC3073895/ Angeloni C, Barbalace MC, Hrelia S. Icariin and Its Metabolites as Potential Protective Phytochemicals Against Alzheimer’s Disease. Front Pharmacol [Internet]. 2019 [cited 2024 Jul 26];10. Available from: /pmc/articles/PMC6433697/ Li X, Wang Y, Shi P, Liu Y, Li T, Liu S, et al. Icariin treatment reduces blood glucose levels in type 2 diabetic rats and protects pancreatic function. Exp Ther Med [Internet]. 2020 [cited 2024 Jul 26];19. Available from: https://pubmed.ncbi.nlm.nih.gov/32256750/ Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7374065","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":502755788,"identity":"a2b5ff98-9df5-4738-8393-2ed5c5c214cf","order_by":0,"name":"Eva Hede","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYDACCQbGx3AOzwHitDAbMzAYkKaFTZo0LfzSzceqC/78YeBvP2PA8OYMEVok5xxLuz2zzYBB4kyOAeOcG0RoMbiRY3abtwHosAM5Bsw8H4jQYg/UUszzx4BB/vwbIrUYSOSYMfOwGYCsA2ohxmESN9KSpXnbjHkMbzwrODiHGO/zz0g++Jnnj5yc3PnkjQ/eHCNCCwzwgIgDJGgYBaNgFIyCUYAPAADjJTM7GWvA1gAAAABJRU5ErkJggg==","orcid":"","institution":"Aalborg University","correspondingAuthor":true,"prefix":"","firstName":"Eva","middleName":"","lastName":"Hede","suffix":""},{"id":502755789,"identity":"336cbaff-9628-4abd-95c7-d2353aecc470","order_by":1,"name":"Annette Burkhart","email":"","orcid":"","institution":"Aalborg University","correspondingAuthor":false,"prefix":"","firstName":"Annette","middleName":"","lastName":"Burkhart","suffix":""},{"id":502755790,"identity":"b7182138-6805-468d-acc0-12d35b59b07d","order_by":2,"name":"Blanca I. Aldana","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Blanca","middleName":"I.","lastName":"Aldana","suffix":""},{"id":502755791,"identity":"f62fff67-dce2-4929-ada4-cadd4edf3e2f","order_by":3,"name":"Kristi A. Kohlmeier","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Kristi","middleName":"A.","lastName":"Kohlmeier","suffix":""},{"id":502755792,"identity":"9aac82f1-0f29-4a24-be62-c7574575b490","order_by":4,"name":"Torben Moos","email":"","orcid":"","institution":"Aalborg University","correspondingAuthor":false,"prefix":"","firstName":"Torben","middleName":"","lastName":"Moos","suffix":""},{"id":502755793,"identity":"d0d73a5a-3d6e-45ac-b605-91957cb4f705","order_by":5,"name":"Maj Schneider Thomsen","email":"","orcid":"","institution":"Aalborg University","correspondingAuthor":false,"prefix":"","firstName":"Maj","middleName":"Schneider","lastName":"Thomsen","suffix":""}],"badges":[],"createdAt":"2025-08-14 12:53:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7374065/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7374065/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89464165,"identity":"541baa93-f11c-4dcd-a7f9-395aea710261","added_by":"auto","created_at":"2025-08-20 08:17:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":124872,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePRISMA 2020 flowchart outlining the identification, screening, exclusion, and inclusion of studies in the systematic review. *Two studies analyzed glucose transporters in both human and mouse brains and are therefore included in both human and rodent studies.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7374065/v1/3200f4fdb11be995f5efb26f.png"},{"id":89463165,"identity":"a26fbbe5-b058-4260-a81b-300ea5e5893c","added_by":"auto","created_at":"2025-08-20 08:09:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":76262,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eGlut1 gene and protein expression in 24-month-old Tg-SwDI mice of mixed sexes compared to age-matched female wild-type controls. Cortical GLUT1 expression was significantly increased compared to wild-type controls at gene- and protein level (A+B) (n=6). Data are presented as mean ± SD, *p-value ≤ 0.05, **p-value ≤ 0.01.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7374065/v1/c88017a993c3343096fa0bc3.png"},{"id":89463167,"identity":"d6775596-d8eb-4310-898a-c5d228a86a32","added_by":"auto","created_at":"2025-08-20 08:09:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":79972,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eGLUT1 gene and protein expression in 4-month-old female 5xFAD mice compared to age-matched wild-type controls. Relative cortical Glut1 gene expression was significantly decreased compared to wild-type controls (n=8) (A). No significant differences in cortical GLUT1 protein concentrations between 4-month-old 5xFAD mice (n=6) and age-matched controls (n=3) were observed. Data are presented as mean ± SD, *p-value ≤ 0.05.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7374065/v1/70c4db2b81ff00ff314741bd.png"},{"id":89463169,"identity":"04bb7635-8a58-47ab-9640-29dfe2ce1082","added_by":"auto","created_at":"2025-08-20 08:09:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":340626,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eSummary of the Alzheimer’s disease (AD) related brain glucose transporter alterations found in the studies included in this review supplemented with original analysis of the Tg-SwDI and 5xFAD mice models. The blood-brain barrier (BBB) specific GLUT1 is localized on the luminal and abluminal surfaces of brain capillary endothelial cells (BCECs) (55kDa isoform) and astrocytes (45 kDa isoform), whereas GLUT2 is mainly expressed on astrocytes, while GLUT3 and GLUT4 are expressed on neurons. GLUT1 and GLUT3 expression are almost consistently decreased in human AD studies, based on 10 and 7 studies, respectively. GLUT2 expression was increased in two human AD studies, while GLUT4 was only examined in one human AD study. GLUT1 and GLUT3 expression were analyzed in 40 and 25 rodent AD studies, respectively, with inconsistent results, though the majority reported an AD-related decrease. GLUT2 and GLUT4 expression were analyzed in 4 and 11 rodent AD studies, with inconsistent results. \u0026nbsp;BCEC: Brain capillary endothelial cell. ↑: Increased expression in AD compared to healthy controls. ↓: Decreased expression in AD compared to healthy controls. ↔: Unaltered expression in AD compared to healthy controls. Percentages indicate number of studies, showing either increased, decreased, or unaltered expression of the specific glucose transporter, out of the included studies that analyzed the specific glucose transporter. Created in Biorender.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7374065/v1/e13b33ec4b7382f87d400ee6.png"},{"id":90769549,"identity":"d68cefc1-e498-4c5e-8b21-b190e3c769f7","added_by":"auto","created_at":"2025-09-07 23:16:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2363897,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7374065/v1/c08339c0-0f0e-4b36-b3d6-24bc66eb17a4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Systematic Review of glucose transporter alterations in human Alzheimer’s disease and rodent Alzheimer’s disease models","fulltext":[{"header":"Background","content":"\u003cp\u003eGlucose is the main energy source of the brain, which requires a constant energy supply to support vital functions such as protein synthesis, maintenance of membrane potentials, and neurotransmission [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. As the local energy stores are limited to minimal glycogen stores in astrocytes, the transport of glucose from the circulation to the central nervous system (CNS) is essential for normal neurological function (Brown \u0026amp; Ransom, 2007; Shah et al., 2012; Sorg \u0026amp; Magistretti, 1991). Unlike most tissues in the body, the brain has a tightly controlled barrier called the blood-brain barrier (BBB) that restricts the free movement of nutrients from the blood into the brain tissue [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In consequence, the brain relies on specialized transporter proteins to ensure sufficient glucose transport into the brain. Glucose uptake from the blood takes place via facilitative transport through the glucose transporter 1 (GLUT1) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The endothelial cells of the brain form the BBB and express the 55 kDa isoform of GLUT1 at both the luminal and abluminal membrane, while astrocytic end-feet, which line the abluminal side of the endothelial cells, express a 45 kDa GLUT1 isoform (Abbott et al., 2009; Simpson et al., 2007). Due to the constant energy consumption of the brain, the concentration gradient drives the facilitative diffusion of glucose towards the CNS, matching the level of neuronal activity and energy use [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWithin the brain, glucose is taken up by astrocytes via GLUT1 or GLUT2 and transported to neurons or directly taken up by neurons via GLUT3 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Intracellularly, glucose is phosphorylated by hexokinase, converted to pyruvate through glycolysis, and used for ATP generation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Astrocytes play a significant role in the transport of glucose within the brain, as they are capable of transporting glucose to the neurons, which is dependent on neuronal activity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Moreover, astrocytes are capable of releasing lactate, a byproduct of glycolysis, into the extracellular space, where it is accessible for neuronal uptake and subsequent conversion to pyruvate for use in energy production (Stobart \u0026amp; Anderson, 2013). In hypoglycemia, resulting from e.g., fasting, where blood glucose levels drop significantly, the brain can utilize lactate and ketone bodies as alternative energy sources (S. C. Cunnane et al., 2016; Henderson, 2004; Lin et al., 2015). These are transported to the brain via monocarboxylate transporters expressed by brain capillary endothelial cells and astrocytes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Contrary to the glucose uptake, the brain uptake of ketone bodies is regulated by the ketone concentration in blood and does not relate to the brain energy consumption [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlterations and dysregulations of brain glucose metabolism have been linked to several neurodegenerative diseases, including Alzheimer\u0026rsquo;s disease (AD), amyotrophic lateral sclerosis, Parkinson\u0026rsquo;s disease, and multiple sclerosis, which strongly emphasizes the importance of normal functioning of glucose metabolism for the brain [\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. AD is the most common cause of dementia with an estimated prevalence of 10 % in pople aged 65 or older (\"2020 Alzheimer's Disease Facts and Figures,\"2020; Hebert et al., 2013). AD is characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Approximately 5 % of A cases are directly attributable to genetic factors, while the majority are sporadic, with unknown causes of disease development. Over the past decades, one of the most extensively studied AD mechanisms is the amyloid cascade hypothesis, which states that neurodegeneration observed in AD is caused by the accumulation of Aβ plaques in various areas of the forebrain [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. According to this hypothesis, abnormal cleavage of the amyloid precursor protein (APP) by β- and γ-secretase through the amyloidogenic pathway leads to the accumulation of Aβ peptides forming beta-sheets, which assemble into oligomers and fibrils forming the Aβ plaques, which are believed to cause neuroinflammation, neuronal dysfunction, tau hyperphosphorylation, and formation of reactive oxygen species ultimately leading to neuronal cell death and brain atrophy [\u003cspan additionalcitationids=\"CR32 CR33 CR34 CR35 CR36 CR37 CR38\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, a growing amount of evidence demonstrates that the Aβ plaque load does not correlate completely with the clinical severity of the disease, as Aβ plaques can also be observed in healthy elderly individuals [\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Furthermore, recently approved anti-Aβ antibody treatments, capable of inducing significant clearance of Aβ, only partially slow disease progression [\u003cspan additionalcitationids=\"CR41 CR42 CR43 CR44 CR45 CR46\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. An alternative to the amyloid cascade hypothesis is the tau hypothesis, which argues that abnormal hyperphosphorylation of tau protein, resulting from the formation of NFTs, is the trigger of AD development [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. While the tau hyperphosphorylation and NFT formation possibly correlate better with the clinical score, halting disease progression has not yet been achieved in clinical studies through Aβ or tau targeting [\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMetabolic changes, involving glucose hypometabolism and mitochondrial dysfunction, are both characteristics of AD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan additionalcitationids=\"CR52\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. These changes have traditionally been considered consequences of neuronal loss and brain atrophy [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, reduced brain glucose uptake has also been found by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in people with an increased risk of developing AD both with and without mild cognitive impairment (MCI), indicating that the metabolic changes precede the development of neuronal dysfunction and brain atrophy (Mosconi et al., 2009, 2013; Protas et al., 2013). Reductions in the cerebral metabolic rate of glucose CMR\u003csub\u003eglc\u003c/sub\u003e could be detected by FDG-PET up to 7 years before developing clinical AD [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Additionally, hypometabolism, but not atrophy, precedes in the precuneus and posterior cingulate cortex in patients with MCI and AD [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e], demonstrating that hypometabolism in AD takes place before the development of brain atrophy and neurological symptoms. Moreover, AD progression increases in patients with hypometabolism following FDG-PET analysis of 551 AD patients, which further emphasizes that hypometabolism plays an important role in the development of AD [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt is currently far from understood what triggers hypometabolism in AD. Decreased levels of GLUT1 at the BBB have been observed in AD patients and the amount of GLUT1 in brain endothelial cells has been shown to correlate with glucose uptake in the brain, demonstrating the essential role of GLUT1 expression for brain glucose uptake [\u003cspan additionalcitationids=\"CR60 CR61 CR62 CR63\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Moreover, GLUT1 deficiency syndrome, a rare genetic metabolic disease caused by GLUT1 haploinsufficiency, is associated with several neurological symptoms including cognitive impairment and microencephaly in humans [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Furthermore, it has been suggested that GLUT1 is involved in the regulation of BBB integrity as studies in zebrafish have demonstrated an essential role of GLUT1 in BBB development [\u003cspan additionalcitationids=\"CR68\" citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. Thus, GLUT1 protein expression and thereby GLUT1-mediated brain glucose uptake could play a significant role in the development of AD. In transgenic mice overexpressing human APP crossed with GLUT1-deficient mice, GLUT1 deficiency accelerated the progression of AD [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. In addition, GLUT1 overexpression induced neuroprotection in a Drosophila model of AD (Niccoli et al., 2016), further emphasizing that GLUT1 expression plays a significant role in AD development. Previous reviews on GLUT alterations and hypometabolism in AD suggested GLUT1 and other brain GLUTs as potential therapeutic targets in AD [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. GLUT alterations were previously reviewed by Szablewski and Kyrtata, who suggested decreased expression of in human AD studies [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. However, AD development and potential treatments are still widely studied in animal models, where the alterations in brain GLUTs vary between different models and analyses. While several studies report reduced expression of GLUTs in rodent models of AD [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan additionalcitationids=\"CR74 CR75\" citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e], other studies were unable to find alterations in the expression of one or more GLUTs when compared to wild-type controls [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan additionalcitationids=\"CR78 CR79\" citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e]. Moreover, an increasing amount of evidence suggests an incomplete causal link between Aβ plaque load and clinical symptoms in AD, which has increased the interest in exploring the metabolic changes associated with disease development [\u003cspan additionalcitationids=\"CR44 CR45 CR46\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs GLUT1 expression has been directly linked to AD progression, this study provides an updated review of GLUT changes in AD patients and in AD rodent models through a systematic review based on analyses of the current literature, with additional analysis of GLUT1 expression in the 5xFAD and Tg-SwDI AD mouse models. Moreover, this review focuses on how GLUT alterations observed in AD patients are replicated in animal models of the disease.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSystematic review\u003c/h2\u003e\u003cp\u003eA systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]. The search strategy focused on articles with the combined mention of \u0026ldquo;glucose transporter proteins, facilitative\u0026rdquo;, \u0026ldquo;glucose transporter\u0026rdquo;, or \u0026ldquo;GLUT\u0026rdquo; and \u0026ldquo;Alzheimer Disease\u0026rdquo;, \u0026ldquo;Alzheimer\u0026rsquo;s disease\u0026rdquo;, or \u0026rdquo;Alzheimers Disease\u0026rdquo;. It was based on a combined Title/abstract and MeSH or Emtree search in Pubmed or Embase, respectively, as specified in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eApplied search strategies for the systematic literature review.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDatabase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSearch strategy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDate\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePubmed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(((\"glucose transport proteins, facilitative\"[MeSH Terms]) OR (glucose transporter[Title/Abstract])) OR (GLUT[Title/Abstract])) AND ((((\"Alzheimer Disease\"[Mesh]) OR (alzheimer disease[Title/Abstract])) OR (alzheimer's disease[Title/Abstract])) OR (alzheimers disease[Title/Abstract]))\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eJuly 1st 2025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEmbase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e('glucose transporter'/exp OR 'glucose transporter':ti,ab,kw OR 'glut':ti,ab,kw) AND ('alzheimer disease'/exp OR 'alzheimer disease':ti,ab,kw OR 'alzheimers disease':ti,ab,kw)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eJuly 1st 2025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eInclusion and exclusion criteria are presented in the PRISMA flowchart (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Identified articles were imported into Mendeley Reference Manager, where duplicates were identified and excluded. Studies were then screened manually by the first author based on titles and abstracts and excluded in cases where CNS GLUT expression was not analyzed or compared to healthy controls, or if the study was not performed in AD patients or animal models of AD. \u003cem\u003eIn vitro\u003c/em\u003e studies were excluded as this review focuses on GLUT alterations in AD patients and animal models. Finally, reviews and conference abstracts were excluded. Studies were included for further assessment when it was impossible to determine eligibility based on title and abstract. The remaining articles were then retrieved and assessed for eligibility. Again, studies were excluded according to the exclusion criteria described above, and the final studies were included as either human or rodent studies.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eGlut1\u003c/b\u003e \u003cb\u003egene expression analysis in Tg-SwDI and 5xFAD mice\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRelative \u003cem\u003eGlut1\u003c/em\u003e mRNA gene expression was analyzed using multiplex probe-based RT-qPCR. RNA was purified from cortical samples from 24-month-old Tg-SwDI mice of mixed sexes (n\u0026thinsp;=\u0026thinsp;6), 4-month-old female 5xFAD mice (n\u0026thinsp;=\u0026thinsp;8), and female wild-type littermates as controls (n\u0026thinsp;=\u0026thinsp;6\u0026ndash;8), using NucleoSpin TriPrep DNA, RNA, and Protein purification kit (Macherey-Nagel, #740966.50), according to the manufacturer's protocol. Briefly, the samples were homogenized with RP1 buffer supplemented with 1% β-mercaptoethanol and filtered through a column filter, followed by the addition of 70% ethanol to bind nucleic acids to a DNA and RNA-binding silica membrane. The membrane was then washed two times with DNA Wash, followed by centrifugation, dried, and incubated for 1 min with DNA Elute, followed by centrifugation to elute DNA. Residual DNA was subsequently digested on the column by the addition of a DNase reaction mixture and 15 min incubation at room temperature. Finally, the silica membrane was washed twice with wash buffer RA2 and RA3, followed by a final wash with wash buffer RA3 and subsequent membrane drying to enable RNA elution with RNase-free H\u003csub\u003e2\u003c/sub\u003eO. Purified RNA was subsequently used as the template for cDNA synthesis with Maxima H Minus First-strand cDNA Synthesis Kit (Thermo Fisher Scientific, #K1651), according to the manufacturer's protocol. In brief, 100 ng RNA was used for the cDNA synthesis reaction with 25 pmol oligo(dT)18 and random hexamer primers, 0.5 mM dNTP Mix, and Maxima H Minus Enzyme Mix in RT buffer. The reaction was incubated in a Veriti\u0026trade; 96-Well Thermal Cycler (Applied Biosystems) with 10 min primer annealing at 25\u0026deg;C followed by polymerization at 50\u0026deg;C for 30 min and termination at 85\u0026deg;C for 5 min. The RT-qPCR reaction was performed using TaqMan Fast Advanced Master Mix (Thermo Fisher Scientific, #4444556), FAM conjugated mouse GLUT1 primer-probe mix (Thermo Fisher Scientific, #4331182, assay ID: Mm00441480_m1), VIC conjugated mouse HPRT1 primer-probe mix (Thermo Fisher Scientific, #4448489, assay ID: Mm03024075_m1), and 5 ng sample cDNA as template, according to the manufacturer's protocol. The reaction was initiated with uracil-N-glycosylase digestion at 50\u0026deg;C for 2 min, to remove potential DNA contaminates, followed by denaturation at 95\u0026deg;C for 2 min and 40 cycles of denaturation for 1 s at 95\u0026deg;C and annealing/extension for 2 min at 60\u0026deg;C on a QuantStudio 6 Flex Real-Time PCR System (ThermoFischer Scientific). Relative gene expression was calculated according to the ΔΔCt method [\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e] based on the obtained threshold cycle (Ct) values using wild-type control samples as the calibrator.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eGLUT1 protein quantification in Tg-SwDI and 5xFAD mice\u003c/h3\u003e\n\u003cp\u003eThe brain GLUT1 protein concentrations were examined in cortical samples from 24-month-old Tg-SwDI mice og mixed sexes (n\u0026thinsp;=\u0026thinsp;6) and whole brain homogenates, cortical brain slices, and hippocampal brain slices from 4-month-old female 5xFAD (n\u0026thinsp;=\u0026thinsp;6) mice and littermate female wild-type controls (n\u0026thinsp;=\u0026thinsp;3\u0026ndash;6). Protein was purified using N-PER Neuronal Protein Extraction Reagent (Thermo Fisher Scientific, #87792), according to the manufacturer\u0026rsquo;s protocol. In brief, samples were homogenized in N-PER, supplemented with cOmplete\u0026trade;, Mini, EDTA-free Protease Inhibitor Cocktail (Merk KGaA, #11836170001), incubated on ice for 10 min and centrifuged at 10,000 x g for 10 min at 4\u0026deg;C to pellet debris. Total protein concentrations were subsequently determined in duplicates using Pierce\u0026trade; BCA Protein Assay Kit (Thermo Fisher Scientific #23225) with 562 nm measurements on an EnSpire Multimode Plate Reader (Perkin Elmer). The GLUT1 protein concentration in the brain samples was analyzed by sandwich ELISA, using a mouse GLUT1 ELISA kit (Nordic BioSite, #EKX-68BIK3-96), according to the manufacturer\u0026rsquo;s protocol. Briefly, protein samples and seven two-fold serial diluted standards ranging from 0.313 to 20 ng/ml were added to primary antibody pre-coated wells and incubated at 37\u0026deg;C for 90 min. The wells were subsequently washed two times, followed by incubation with Biotin-labeled secondary antibody at 37\u0026deg;C for 60 min. Then, wells were washed three times, incubated with HRP-Streptavidin Conjugate at 37\u0026deg;C for 30 min, and subsequently washed five times. Finally, the wells were incubated with TMB Substrate for 20 min at 37\u0026deg;C after which Stop Solution was added followed by OD measurement at 450 nm on an EnSpire Multimode Plate Reader (Perkin Elmer). Samples and standards were all measured in duplicates and the data was subsequently analyzed in GraphPad Prism 10.0.2 using a 4-parameter sigmoidal logistics curve to interpolate the sample concentrations based on the standard curve.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eAll data sets were initially tested for normality using the Sharpiro-Wilk normality test and for equal variance using an F-test. Data sets for relative gene expression and cortical protein expression in 5xFAD mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC\u0026thinsp;+\u0026thinsp;D) did not pass the normality test and were therefore analyzed by the non-parametric Mann-Whitney U test. Homogeneity of variance was not met in the data set for relative gene expression in Tg-SwDI mice, which was therefore also analyzed with the Mann-Whitney U test (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The remaining data sets were normally distributed with homogeneity of variance and were therefore analyzed by parametric unpaired two-tailed t-tests (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-B).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e The systematic literature review resulted in 15 human and 45 rodent studies analyzing the expression of GLUTs in AD. Both human and rodent studies exclusively included postmortem studies of different brain regions. The most studied CNS transporter was GLUT1, which was studied in 10 of the 15 human studies and 37 out of the 49 rodent studies. The second most studied transporter was GLUT3, primarily responsible for glucose uptake in neurons. GLUT3 expression was analyzed in seven human and 25 rodent studies. The insulin-dependent neuronal glucose transporter, GLUT4, was studied in a single human study and 13 rodent studies, while the astrocytic glucose transporter, GLUT2, was studied in two human studies and six rodent studies. Finally, a single rodent study examined the more recently discovered GLUT12. While GLUT12 is mainly expressed in peripheral tissues, expression within the brain was demonstrated by RNA sequencing, primarily in oligodendrocyte progenitor cells and astrocytes [\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e, \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]. The expression of GLUT12 has been linked to insulin sensitivity and the development of cancer and diabetes [\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]. However, the function of GLUT12 in the brain remains unclear.\u003c/p\u003e\n\u003ch3\u003eEvidence of GLUT alterations from human studies\u003c/h3\u003e\n\u003cp\u003eMost human studies analyzing GLUT1 expression observed a reduction in various brain regions, such as the hippocampus and cerebral cortex, in tissue samples obtained from AD patients compared to healthy age-matched controls. An exception quantified GLUT1 in microvessels using immunohistochemistry combined with stereology, which showed an increase in GLUT1 intensity was noted in the hippocampal CA1 region of AD patients when compared to controls, but no differences in the CA2 region were detected [\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e]. The alterations in GLUTs reported in the human studies are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Altered GLUT expression in AD was initially discovered by Kalaria and Harik in microvessels, cerebral cortex, and hippocampus by demonstrating reduced H\u003csup\u003e3\u003c/sup\u003e glucose binding as well as reduced levels of hexose transport proteins in human postmortem tissue [\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e]. In a subsequent study, Harik et al. found a 50 % reducion in the density of glucose transporters in cerebral microvessels in postmortem tissue from AD patients compared to age-matched controls. This was further supported by subsequent immunolabeling, showing significantly lower GLUT1 intensities in hippocampal tissue from AD patients compared to age-matched controls [\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e]. Kawai et al. further demonstrated reduced GLUT1 density related to the presence of Aβ plaques in hippocampal sections of AD patients [\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e]. Simpson et al. demonstrated a reduction in both the endothelial GLUT1 and neuronal GLUT3 in cortical AD samples compared to healthy controls [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e], which was consistent with findings by Harr et al. demonstrating a 49.5 % reduction in GLUT immunoreactivity in the hippocampal dentate gyrus in AD brains [\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e]. In addition, An et al. demonstrated reduced GLUT3 levels by LC-MS/MS in frontal gyrus tissue from AD patients compared to healthy controls when adjusting for neuronal nuclear protein levels, age at death, and sex [\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e]. Their results also demonstrated a correlation between GLUT3 reductions and the severity of Aβ and NFT pathology. The GLUT1 reductions were further confirmed in more recent studies by Wang et al.[\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e] and Leclerc et al.[\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e]. In the study by Wang et al. GLUT1 expression in the cortex and hippocampus areas, quantified from immunohistochemical staining, was markedly reduced in AD patients compared to controls [\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e]. Leclerc et al. analyzed GLUT1 protein levels in microvessel extracts from the parietal cortex by Western Blot and found GLUT1 reductions in AD samples compared to controls, which correlated with the levels of neuritic plaques and cerebrovascular β-secretase-derived fragments. Moreover, they found an association between GLUT1 reductions and cognitive scores [\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMooradian et al. observed a reduction of GLUT1 protein in the cortex of AD brains, whereas the GLUT1 mRNA expression was equal to that in healthy controls, indicating post-transcriptional regulation of GLUT1 expression[\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e] Moreover, Jin et al. examined the GLUT3 mRNA expression in the frontal cortex and found reduced mRNA levels in cortical tissue from AD patients compared to age-matched controls[\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e] consistent with reduced GLUT3 protein levels found by others [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e, \u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e, \u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e]. Unfortunately, Jin et al. did not examine the GLUT3 protein levels, making it difficult to conclude on possible post-transcriptional regulation of GLUT3 expression.\u003c/p\u003e\u003cp\u003eLiu et al. analyzed the expression of GLUT1, GLUT2, GLUT3, and GLUT4 in postmortem tissue from AD patients and found significantly decreased GLUT1 and GLUT3, increased GLUT2, and unaltered GLUT4 in tissue from AD patients compared to age-matched controls [\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e]. These findings were confirmed in a later study by the same group, demonstrating the expression of GLUT1, GLUT2, and GLUT3 in postmortem tissue from AD patients with or without diabetes mellitus [\u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e]. They also found a significantly reduced expression of GLUT1 and GLUT3 in AD, while the GLUT2 expression was significantly increased in AD compared to healthy controls. In tissue from AD patients with diabetes mellitus, they also found reduced GLUT3 and increased GLUT2. However, contrary to the reduced expression of GLUT1 in AD patients without diabetes mellitus, the GLUT1 expression was unaltered in AD patients with diabetes compared to controls.\u003c/p\u003e\u003cp\u003eOverall, the human studies analyzing GLUT alterations in AD almost consistently observed AD-related reduction in GLUT1 and GLUT3 protein expression analyzed by immunohistochemistry, Western Blotting, and LC-MS/MS in various brain regions, except for a single study finding increased GLUT1 expression in microvessels of the hippocampal CA1 region. Only a single study examined the GLUT2 expression in AD and found an AD-related increase in GLUT2 protein expression. Moreover, results from several studies demonstrate a correlation between the reductions in GLUT1 and GLUT3 protein expression and AD pathology.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eOverview of glucose transporter alterations found in human studies, comparing AD patients to healthy age-matched controls. AD: Alzheimer\u0026rsquo;s disease, DMT2: Diabetes Mellitus type 2, WB: Western Blot, NB: northern blot, IHC: immunohistochemistry, LC-MS/MS: liquid chromatography with tandem mass spectrometry.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSamples\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMethods\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSubjects\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGLUT1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGLUT2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eGLUT3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eGLUT4\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKalaria et al. 1989\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem brain tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH3 Glucose binding assay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26 AD patients and 23 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHarik et al. 1991\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem cerebral microvessels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH3 Glucose binding assay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 AD patients and 13 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKawai et al. 1990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem hippocampus sections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 AD cases. (No controls)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHorwood et al. 1994\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem hippocampal tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 AD patients and 8 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSimpson et al. 1994\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 AD patients and 12 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHarr et al. 1995\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem hippocampal tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 AD patients and 8 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMooradian et al. 1997\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem cerebral microvessels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWB and NB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 AD patients and 7 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiu et al. 2008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem frontal cortex tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 AD patients and 7 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiu et al. 2009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem frontal cortex tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 AD patients, 8 AD\u0026thinsp;+\u0026thinsp;DMT2 patients, and 7 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJin et al. 2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem frontal cortex tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eqPCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 AD patients and 7 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBurke et al. 2014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem hippocampal tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 AD patients and 13 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAn et al. 2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem brain tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLC-MS/MS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 AD patients and 14 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNam et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem frontal cortex tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 AD patients and 10 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWang et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem cortical and hippocampal tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 AD patients and 5 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLeclerc et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePostmortem parietal cortex tissue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20 AD patients, 20 MCI patients, and 20 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eEvidence of GLUT alterations in rodent AD models\u003c/h2\u003e\u003cp\u003e The 50 rodent studies included in this review consisted of 11 studies in five different rat AD models and 39 studies in 13 different mouse AD models. While most mouse studies analyzing the GLUT expressions were performed in transgenic mouse models, the rat studies were mainly performed in sporadic AD models. The rat studies almost consistently revealed reduced GLUT1, GLUT3, and GLUT4 expression and increased GLUT2 expression in AD rats compared to wild-types, while the AD mouse studies found both reduced, increased, and unchanged GLUT1-4 expression.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eGLUT alterations in mouse models based on the APP transgene\u003c/h3\u003e\n\u003cp\u003eEight of the included mouse studies were performed in transgenic AD models based on the human APP transgene bearing one or more mutations linked to familial AD (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Kouznetsova et al. studied AD-related cerebral cortical capillary changes in Tg2576 AD mice and found reduced cortical GLUT1 capillary density by immunohistochemistry in 18-month AD mice compared to wild-type controls [\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e]. These mice overexpress the APP transgene bearing the Swedish mutation under the control of the hamster prion protein promoter and develop synapse loss from 4.5-month-old mice followed by cognitive impairment between 6 and 12 months, gliosis from 10\u0026ndash;16 months, and Aβ plaques from 11\u0026ndash;13 months [\u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e]. Consistent with the initial findings by Kouznetsova et al. a later study by the same group demonstrated reduced GLUT1 expression in 18-month-old Tg2576 mice by immunocytochemistry when Aβ plaque load was considerable, but no changes in GLUT1 at 10 months, which is at the beginning of plaque deposition, indicating that Aβ accumulation may contribute to GLUT1 reductions [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]. In a different study, Winkler et al. examined the effect of GLUT1 deficiency on the progression of AD development in Tg2576 mice. They did not find any significant differences in cortical and hippocampal GLUT1 protein intensities in presymptomatic 6-month-old Tg2576 mice compared to wild-type controls using immunohistochemistry, further supporting a possible correlation between Aβ pathology and GLUT1 reductions [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. However, induced GLUT1 deficiency in the Tg2576 mice, accelerated AD symptoms and pathology, indicating that GLUT1 reduction can also accelerate the Aβ pathology. Combined, these studies indicate that Aβ pathology can affect GLUT1 expression and that reduction of GLUT1 can also accelerate AD pathology.\u003c/p\u003e\u003cp\u003eUm et al. and Cho et al. analysed 13-month-old APPsw-NSE mice[\u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e] which overexpress the same APP transgene bearing the Swedish mutation as the Tg2576 mice, but under the control of the neuron-specific enolase (NSE) promoter, resulting in the development of Aβ-plaque like depositions already from two months of age, and found significantly reduced GLUT1 expression by Western Blotting found significantly reduced GLUT1 expression by Western Blotting (Hwang et al., 2004; J. H. Kim et al., 2012). Additionally, Shang et al. found reduced cortical GLUT1 intensities in immunohistochemical staining in 12-month-old male APP23 mice based on another APP transgene isoform bearing the Swedish mutation under the control of the murine Thy1 promoter [\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e]. These mice present with cognitive impairment as early as three months of age followed by gliosis and amyloid plaques at 6 months and neuronal loss developing around 14\u0026ndash;18 months [\u003cspan additionalcitationids=\"CR108 CR109\" citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e]. Merlini et al. analyzed cortical and hippocampal GLUT1 and GLUT3 alterations by Western Blotting in 9\u0026ndash;13 month-old ArcAβ mice[\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e] containing the human APP transgene with the Swedish mutation and an additional Arctic mutation [\u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e]. At 6 months of age, these mice develop cognitive impairment followed by plaques between 9 and 15 months, and a reduced endothelial GLUT1 expression compared to wild-type littermates was seen, no significant difference in GLUT3 expression was seen between genotypes, contrary to the observations from human AD studies described above [\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo support existing findings of GLUT1 expression in AD mouse models, we analyzed Glut1 gene and protein expression in 24-month-old Tg-SwDI mice of mixed sexes with marked pathology and neuroinflammation[\u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e] and compared these levels to age-matched female wild-type controls. The Tg-SwDI mice express the human transgene for APP with the Swedish mutation along with the Dutch, and Iowa mutations, related to familial cerebral amyloid angiopathy (CAA), under the control of the Thy1.2 promoter [\u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e]. CAA is an evident feature of AD, defined by the progressive accumulation of Aβ protein within the brain vasculature, leading to an increased risk of hemorrhages [\u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e, \u003cspan citationid=\"CR116\" class=\"CitationRef\"\u003e116\u003c/span\u003e]. These transgenic mice present with Aβ plaques, significant CAA, and cognitive impairment from three months of age, and gliosis at six months of age(Davis et al., 2004; Miao et al., 2005; F. Xu et al., 2007). In contrast to many of the listed studies, we found a significant 22.9-fold increase in cortical \u003cem\u003eGlut1\u003c/em\u003e gene expression (P\u0026thinsp;=\u0026thinsp;0.0022) and a significant increase in protein concentration from 5.66 ng GLUT1 per mg total protein in wild-types to 7.33 ng GLUT1 per mg protein in Tg-SwDI mice (P\u0026thinsp;=\u0026thinsp;0.0398) analyzed with enzyme-linked immunosorbent assay (ELISA) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAll the results from studies performed in transgenic mouse models based on a mutated human APP gene show an AD-related decrease in GLUT1 expression in whole brain homogenates, cortex, and hippocampus analyzed by Western Blot and immunohistochemistry, possibly following Aβ plaque formation, except for our analysis of the Tg-SwDI mouse which demonstrated a significant increase in cortical GLUT1 gene and protein at 24 months compared to controls, when analyzed by qPCR and ELISA (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, B). Interestingly, this was also the only study analyzing the GLUT1 expression in an AD model with CAA pathology, which could suggest that the microvessels are affected differently in this case compared to models with primarily parenchymal Aβ deposition. Moreover, the Tg-SwDI mice develop gliosis at 6 months of age(Miao et al., 2005), like the APP23 mice [\u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e], whereas this does not occur until the age of 10 months in the Tg2576 mice[\u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e] and was not reported in the APPsw-NSE and ArcAβ mice. When combined with the older age of the Tg-SwDI mice in the present study, the level of gliosis could be markedly higher in these mice, which might contribute to a higher expression of the astrocytic GLUT1 isoform simply due to an increased number of astrocytes or potentially increased expression in activated microglia [\u003cspan citationid=\"CR118\" class=\"CitationRef\"\u003e118\u003c/span\u003e]. However, this would be inconsistent with the decreased GLUT1 expression observed in postmortem samples from aged human AD patients. Additionally, the present study in Tg-SwDI mice was the only study analyzing the protein concentrations by ELISA, which is characterized by higher accuracy and reliability compared to Western Blots[\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e] and likely also more sensitive than quantitative immunohistochemistry, which is generally merely subjective as small differences in exposure time or selected areas for quantification can have a substantial impact on the results [\u003cspan citationid=\"CR120\" class=\"CitationRef\"\u003e120\u003c/span\u003e]. A disadvantage of the ELISA used in the present study is that both the endothelial and astrocytic GLUT1 isoforms are detected, whereas these can be differentiated on the Western Blots due to the size differences. However, only two of the studies analyzing GLUT1 expression by Western Blot specified that they were quantifying the endothelial 55 kDa isoform [\u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e, \u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e], while the remaining two studies did not specify whether the quantification was based on one or both isoforms [\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e], which makes it difficult to draw any conclusions regarding the possible influence of astrocytic GLUT1 on the reported GLUT1 protein levels. Results regarding the GLUT3 expression in APP-based mouse models were inconsistent, as the two studies investigating GLUT3 expression found an AD-related decrease and unaltered GLUT3 expression when analyzed by Western Blot [\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e, \u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e]. While the study by Gil-Iturbe et al., demonstrating a reduction in GLUT3 expression, was performed in female mice, the sex of the animals was not reported in the study demonstrating unaltered GLUT3 by Merlini et al. Thus, it is not possible to draw any general conclusions regarding the GLUT3 expression in the APP-based mouse models from these results.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eGLUT alterations in mouse models based on APP and PSEN1 mutations\u003c/h3\u003e\n\u003cp\u003e16 mouse studies were conducted using transgenic AD models expressing both human APP and the γ-secretase subunit presenilin 1 (PSEN1) genes, with mutations linked to familial AD (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). 10 mouse studies examined the expression of CNS glucose GLUTs in the APP/PS1dE9 mouse model containing a chimeric mouse/human APP transgene bearing the Swedish mutation and human PSEN1 lacking exon 9 (dE9) under the control of the mouse prion protein promoter [\u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e]. These mice exhibit synaptic loss in the hippocampal area starting from 4 months of age, followed by gliosis and Aβ plaque development from 6 months, and neuronal loss at 8 months, culminating in cognitive impairment at 12 months [\u003cspan additionalcitationids=\"CR123\" citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e]. Gil-Iturbe et al. analyzed the cortical expression of both GLUT1, GLUT3, GLUT4, and GLUT12 in 16-month-old female Tg2576 mice and 16-month-old female double transgenic APP/PS1dE9 mice by Western Blot. They observed reduced GLUT1 and GLUT3 expression, increased GLUT12 expression, and unchanged GLUT4 expression in both animal models compared to controls [\u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e]. While the AD-related GLUT1 reduction observed by Gil-Iturbe et al. was consistent with the findings from human studies and other APP-based mouse models, the decrease in GLUT3 expression was also consistent with the findings from human studies, but contrary to the unaltered expression found by Merlini et al. in the ArcAβ APP mice. In a more recent study, Ma et al. were also able to detect a significantly reduced GLUT1 expression in brain homogenates from 14-month-old male APP/PS1dE9 mice compared to wild-type controls by Western Blot analysis (Ma et al., 2022). Hooijman et al. analyzed the hippocampal GLUT1 protein expression in 8- and 18-month-old APP/PS1dE9 mice by immunohistochemistry [\u003cspan citationid=\"CR126\" class=\"CitationRef\"\u003e126\u003c/span\u003e], and found significantly reduced GLUT1 protein levels with unchanged capillary density at 18 months but no significant GLUT1 changes at 8 months, compared to controls, even though Aβ plaques and gliosis is present at this age. Thus, these findings conflict with the suggested correlation between Aβ plaque development and GLUT1 reductions. Both Huang et al. and Wang et al. examined the GLUT1 expression in 2-, 4-, and 9-month-old APP/PS1dE9 mice by immunohistochemistry and found a significantly reduced GLUT1 intensity in the hippocampus area at 4 and 9 months compared to controls, but not in 2-month-old mice [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e]. These findings thus support a possible correlation between GLUT1 reductions and AD pathology, indicating that GLUT1 reduction can precede plaque development in this model, as the Aβ plaques are not present in the 4-month-old mice.\u003c/p\u003e\u003cp\u003eUsing the same mouse model, APP/PS1dE9, Chen et al. investigated the effects on cognition of the traditional Chinese medicine, Banxia Xiexin decoction and found reduced hippocampal levels of both GLUT1 and GLUT3 by Western Blot in 6-month-old untreated AD mice compared to wild-type controls [\u003cspan citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e]. Guo et al. also reported reduced GLUT3 levels in the hippocampus and cortex of 6-month-old APP/PS1dE9 mice compared to controls when examined by immunohistochemistry [\u003cspan citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e]. On the contrary, Zerbi et al. did not find any AD-related differences in GLUT1 expression in hippocampal areas in 8- and 12-month-old AD mice, when analyzed by immunohistochemistry [\u003cspan citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e] and Zhang et al. did not find any significant difference in the hippocampal GLUT3 expression in 13-month-old APP/PS1dE9 mice when analyzed with Western Blot [\u003cspan citationid=\"CR130\" class=\"CitationRef\"\u003e130\u003c/span\u003e]. Finally, Khandelwal et al. analyzed the relative gene expression of \u003cem\u003eGlut1, Glut3\u003c/em\u003e, and \u003cem\u003eGlut4\u003c/em\u003e in 8-month-old APP/PS1dE9 mice and found increased relative GLUT1 and GLUT4 expressions in transgenic mice compared to wild-type controls, while there was not any significant difference in the relative \u003cem\u003eGlut3\u003c/em\u003e gene expression [\u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e]. However, this was the only study examining the gene expression, and the inconsistency with results from other studies examining the protein levels could be due to post-transcriptional regulation. Nevertheless, while six of the eight studies examining GLUT1 expression in the APP/Ps1dE9 model find an AD-related reduction corresponding to the findings from human studies, the results from the studies performed in this model are generally inconsistent regarding the expression of GLUTs and the correlation between this and AD pathology. This could be ascribed to differences in age, sex or brain regions analyzed. The studies reporting increased or no differences in AD-related GLUT1 or GLUT3 expression analyzed hippocampal and whole brain homogenates from 8- to 13-month-old male mice or mice of unreported sex [\u003cspan additionalcitationids=\"CR130\" citationid=\"CR129\" class=\"CitationRef\"\u003e129\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e], while the remaining studies, finding AD-related GLUT1 or GLUT3 reductions analyzed hippocampal, cortical and whole brain homogenates from 4- to 14-month-old male mice or mice of unreported sex [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e, \u003cspan additionalcitationids=\"CR126 CR127\" citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR128\" class=\"CitationRef\"\u003e128\u003c/span\u003e, \u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e]. It is therefore not possible to explain the inconsistent results between the studies by differences in age, sex or brain regions analyzed. On the contrary, all studies, except one, analyzed the protein expression levels based on immunohistochemistry or Western Blots, which are associated with a higher variability between tests compared to ELISA for protein quantification [\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e]. The inconsistent results from studies in the APP/Ps1dE9 model make it difficult to draw any clear conclusions regarding the expression of GLUTs in this model and how this would correlate with the findings from human studies.\u003c/p\u003e\u003cp\u003eSix of the 39 mouse studies analyzed the expression of GLUT in the APP/PS1 mouse model. These mice contain the human APP transgene bearing the Swedish mutation and the human PSEN1 transgene bearing an L166P mutation under the control of the Thy1 promotor. These mice develop Aβ plaques and gliosis from 6 weeks of age in the cortex and at 3 months in the hippocampus, synaptic loss at 10 weeks, cognitive impairment at 7 months, and neuronal loss in areas with high neuronal density at 17 months [\u003cspan additionalcitationids=\"CR134\" citationid=\"CR133\" class=\"CitationRef\"\u003e133\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR135\" class=\"CitationRef\"\u003e135\u003c/span\u003e]. Pang et al. and Qin et al analyzed the expression of GLUT1 and GLUT3 by Western Blot in male APP/PS1 mice [\u003cspan citationid=\"CR136\" class=\"CitationRef\"\u003e136\u003c/span\u003e, \u003cspan citationid=\"CR137\" class=\"CitationRef\"\u003e137\u003c/span\u003e] and described reduced GLUT1 and GLUT3 levels in the cortex and hippocampus of 8-month-old mice and the hippocampus of 6-month-old mice, respectively. These findings were consistent with results from a study by Wu et al. investigating the effects of progesterone on neuronal glucose. They found significantly reduced GLUT3 and GLUT4 protein levels in the cortex of 6-month-old male untreated APP/PS1 mice compared to wild-type controls using both immunocytochemistry and Western Blot [\u003cspan citationid=\"CR138\" class=\"CitationRef\"\u003e138\u003c/span\u003e]. Moreover, Wang et al. investigated the effect of the traditional Chinese medicine Jiaotaiwan on brain glucose metabolism in 3-month-old male APP/PS1 mice. They demonstrated reduced GLUT1, 3, and 4 gene and protein expression in cortex and hippocampus of AD mice compared to wild-type controls, when analyzed by Western Blot and qPCR [\u003cspan citationid=\"CR139\" class=\"CitationRef\"\u003e139\u003c/span\u003e]. On the contrary, a fourth study by He et al. showed no significant difference between the hippocampal GLUT1, 3, or 4 expressions in 6-month-old male APP/PS1 mice and wild-type controls when analyzed by Western Blotting [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]. Conversely, they found a significantly increased GLUT1 and GLUT3 expression in the APP/PS1 mice with diabetes mellitus, induced by intraperitoneal streptozotocin (STZ) injection, compared to untreated APP/PS1 mice, implicating the role of insulin on GLUT1 regulation, which was also observed in humans by Liu et al [\u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e]. Qi et al. examined the effects of age and sex on hypothalamic glucose alterations in APP/PS1 mice [\u003cspan citationid=\"CR140\" class=\"CitationRef\"\u003e140\u003c/span\u003e]. Consistent with the findings by He et al., they demonstrated unchanged GLUT3 expression in AD mice compared to wild-type controls. However, they observed an increased GLUT1 expression in 3-month-old AD males and 14-month-old AD females, when compared to age-matched controls, while the GLUT1 expression was unaltered in 14-month-old males and 3-month-old females [\u003cspan citationid=\"CR140\" class=\"CitationRef\"\u003e140\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe inconsistency in observed GLUT1, GLUT3, and GLUT4 expressions could not be explained by variations in model, age, sex, brain region, or analysis method in this case, as both He et al. and Qin et al. analyzed hippocampal tissue in 6-month-old male mice by Western Blot with different results. However, the quantification of GLUT protein levels was based on brain tissue from three mice in the study by He et al., while tissue from five, six, and 12 mice was used for quantification in the studies by Pang et al., Qin et al., and Wu et al., respectively [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan additionalcitationids=\"CR137\" citationid=\"CR136\" class=\"CitationRef\"\u003e136\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR138\" class=\"CitationRef\"\u003e138\u003c/span\u003e]. Thus, the studies finding an AD-related reduction in the expression of GLUTs likely had a greater sensitivity to detect differences when compared to the study by He et al. Moreover, in the study by He et al., the GLUT protein levels were normalized to GAPDH protein levels, while beta-actin protein levels were used for normalization in the other studies performed in APP/PS1 mice. These parameters, combined with relatively lower reliability between experiments of Western Blots compared to other methods for protein quantification, could perhaps explain the inconsistencies in observed GLUT1, GLUT3, and GLUT4 expression in the APP/PS1 model.\u003c/p\u003e\u003cp\u003eTo sum up, three of the four studies investigating GLUT expression in APP/PS1 mice found reduced GLUT1, GLUT3, and GLUT4 expressions when analyzing the hippocampus and cortex of 6- and 8-month-old AD mice compared to controls using immunohistochemistry and Western Blot. These results are consistent with the findings from human studies. One study did not find any AD-related differences in the hippocampal expression of these transporters when examined by Western Blot in 6-month-old mice, possibly due to the lower sensitivity of this study, combined with a lower method-related reliability [\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFour studies examined the GLUT expression in the 5xFAD mouse model containing five different mutations linked to familial AD. This model is based on the human APP transgene with the Swedish, London, and Florida mutations and the human PSEN1 transgene with the L286V and M146L mutations. These mice develop Aβ plaques and gliosis as early as 2 months, followed by synaptic loss and cognitive impairment from 4 months of age and neuronal losses at 6 months old [\u003cspan citationid=\"CR141\" class=\"CitationRef\"\u003e141\u003c/span\u003e]. Ahn et al studied impaired cerebrovascular structures in 5xFAD mouse brains and found reduced GLUT1 intensities in the cortex and hippocampus in 4.5- and 9- month-old 5xFAD mice compared to wild-type controls when studied by Western Blot and immunohistochemistry [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]. On the contrary, Puris et al. did not find any significant differences in cortical GLUT1 protein expression in 7-month-old male 5xFAD mice but reported increased GLUT1 expression in 7-month-old female 5xFAD mice compared to controls when analyzing membrane fractions by LS-MS/MS [\u003cspan citationid=\"CR142\" class=\"CitationRef\"\u003e142\u003c/span\u003e]. Kim et al. analyzed the expression of GLUT1, GLUT2, and GLUT3 in a study investigating the effect of carboxy-dehydroevodiamine-HCl on AD-related GLUT alterations in the 5xFAD mouse model. Using Western Blot, they were able to demonstrate reduced GLUT1 and GLUT3 expressions and increased GLUT2 expression in brain homogenates from 6-month-old untreated 5xFAD mice of unreported sex compared to wild-type controls [\u003cspan citationid=\"CR143\" class=\"CitationRef\"\u003e143\u003c/span\u003e]. These findings were further supported by a fourth study by Nam et al., demonstrating reduced cortical GLUT3 expression in 6 to 11-month-old male 5xFAD mice by immunohistochemistry [\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn addition, we analyzed GLUT1 gene and protein expression in 4-month-old female 5xFAD mice, compared to age-matched wild-type controls. At this age, these mice have developed both AD characteristic pathology and cognitive impairment. However, contrary to the findings in previous studies, our analysis shows a significant decrease in \u003cem\u003eGlut1\u003c/em\u003e gene expression in the cortex of 4-month-old 5xFAD mice (P\u0026thinsp;=\u0026thinsp;0.0207), while no differences were observed in cortical protein concentrations when analyzed by ELISA (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Similar analysis of GLUT1 concentration in whole brain homogenates and hippocampal tissue from 4-month-old female 5xFAD mice also did not show any AD-related alteration of protein concentrations (data not shown). The difference between the GLUT1 gene and protein alterations found in the present study could indicate a post-transcriptional regulation of the GLUT1 expression. However, it could also be due to undetectable GLUT1 protein reductions at 4 months of age in the 5xFAD model, as the qPCR used for analysis of gene expression is generally considered a more sensitive method than the ELISA used for protein detection [\u003cspan citationid=\"CR144\" class=\"CitationRef\"\u003e144\u003c/span\u003e]. This interpretation agrees with the studies by Ahn et al. and Kim et al. that report a reduced GLUT1 protein expression by immunohistochemistry and Western Blot in older mice, in which GLUT1 reduction might be more prominent [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e, \u003cspan citationid=\"CR143\" class=\"CitationRef\"\u003e143\u003c/span\u003e]. However, this explanation is contradicted by the results of Puris et al., demonstrating unaltered GLUT1 in 7-month-old male 5xFAD mice and increased GLUT1 in 7-month-old female mice by LC-MS/MS [\u003cspan citationid=\"CR142\" class=\"CitationRef\"\u003e142\u003c/span\u003e]. Taken together, it remains difficult to draw any general conclusions regarding the expression of GLUTs in the 5xFAD mouse model based on these findings due to the varying age, sex, brain regions, and methods used.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eGLUT alterations in mouse models based on APP, PSEN1, and MAPT mutations\u003c/h2\u003e\u003cp\u003eFive studies examined the GLUT expression in the triple transgenic mouse model 3xTg (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), which is based on the expression of three human transgenes for both APP with the Swedish mutation, PSEN1 with a M146V mutation, and microtubule-associated protein (MAPT) with a P301L mutation linked to frontotemporal dementia [\u003cspan citationid=\"CR145\" class=\"CitationRef\"\u003e145\u003c/span\u003e]. These mice develop cognitive impairment at 4 months of age followed by amyloid plaques and gliosis between 6 and 7 months and extensive tau pathology at the age of 12 months [\u003cspan additionalcitationids=\"CR146\" citationid=\"CR145\" class=\"CitationRef\"\u003e145\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR147\" class=\"CitationRef\"\u003e147\u003c/span\u003e]. Do et al., found reduced GLUT1 expression in the capillaries of 18-month-old 3xTg mice by Western Blot when compared to wild-type controls. These findings were consistent with a more recent study by Yan et al, demonstrating significantly reduced GLUT1 and GLUT3 in the cortex of 8-month-old male 3xTg mice compared to wild-type controls by Western Blot [\u003cspan citationid=\"CR148\" class=\"CitationRef\"\u003e148\u003c/span\u003e]. However, a study by Chen et al. revealed no significant differences in GLUT1, GLUT2, and GLUT3 in brain homogenates from 9-month-old female 3xTg mice when analyzed by Western Blot, which could indicate sex related differences in this model [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e]. Li et al. analyzed the hippocampal GLUT4 expression in 11-month-old female 3xTg mice by Western Blot in a study investigating the protective effects of enhancing glucagon-like peptide 1 signaling with a dipeptidyl peptidase IV inhibitor and found a significantly reduced GLUT4 expression in 3xTg mice compared to controls[\u003cspan citationid=\"CR149\" class=\"CitationRef\"\u003e149\u003c/span\u003e] In summary, the results from studies performed in the triple transgenic 3xTg mouse model demonstrate reduced expression of GLUT1, 3, and 4 in cortex, capillaries, and hippocampus in male and female mice analyzed by Western Blot [\u003cspan additionalcitationids=\"CR150\" citationid=\"CR149\" class=\"CitationRef\"\u003e149\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR151\" class=\"CitationRef\"\u003e151\u003c/span\u003e], while one study did not find any alterations of GLUT1-3 in whole brain homogenates from female mice when analyzed by Western Blot [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eGLUT alterations in transgenic mouse models based on other mutations\u003c/h2\u003e\u003cp\u003eFour studies examined the expression of GLUTs in transgenic mouse models that are not based on APP or PSEN1 mutations (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Lee et al. examined the expression of GLUT1, GLUT 3, and GLUT4 in membrane proteins in 12-month-old NSE/hPS2 mice by Western Blot. These mice carry the human transgene for gamma-secretase subunit presenilin 2 (PSEN2) with the N141I mutation driven by the NSE promotor. They develop behavioral deficits by 12 months and altered Aβ42 levels, but no neuropathology has been observed [\u003cspan citationid=\"CR152\" class=\"CitationRef\"\u003e152\u003c/span\u003e]. Nevertheless, Lee et al. found significantly reduced GLUT1 and GLUT 3 expressions in 12-month-old NSE/hPS2 mice compared to wild-type controls, while GLUT4 expression was unchanged [\u003cspan citationid=\"CR153\" class=\"CitationRef\"\u003e153\u003c/span\u003e]. Zhang et al. examined the expression of GLUT1, 3, and 4 in the hippocampus of 8-month-old P301S mice, bearing the MAPT transgene with the P301S mutation, and found significantly reduced expression of all transporters when examined by Western Blot. These mice do not develop plaques, but cognitive impairment has been demonstrated from 2.5 months of age, and NFTs are detected at 4 months, while gliosis develops from 5 months [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR154\" class=\"CitationRef\"\u003e154\u003c/span\u003e, \u003cspan citationid=\"CR155\" class=\"CitationRef\"\u003e155\u003c/span\u003e]. Hendrix et al. examined the expression of GLUT1, GLUT2, GLUT3, and GLUT4 in a BRI-Aβ42 mouse model overexpressing human Aβ42 without an effect on APP expression, which results in plaque development and gliosis from 3 months of age [\u003cspan citationid=\"CR156\" class=\"CitationRef\"\u003e156\u003c/span\u003e]. Total cortical protein levels of GLUT1, GLUT3, and GLUT4 did not differ, while total GLUT2 protein was significantly reduced in BRI-Aβ42 compared to controls when analyzed by an automated capillary Western Blot assay. However, decreased astrocytic 45-kDa GLUT1 expression was noted when analyzing plasma membrane fractions, while the plasma membrane fractions of endothelial 55-kDa GLUT1, GLUT3, and GLUT4 were unchanged and undetectable for GLUT2 [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]. Finally, Janssen et al. examined hippocampal GLUT1 intensities in ApoE4 knock-in and ApoE-deficient mice in a study evaluating the effects of a high-fat diet in this model. They did, however, not find any differences in the hippocampal GLUT1 levels between ApoE4 knock-in, ApoE-deficient, and wild-type mice when examined by immunohistochemistry [\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOverall, the results from mouse studies examining the expression of GLUTs in transgenic AD models show a tendency towards decreased GLUT1 and GLUT3 expressions, consistent with the observations in human studies. Moreover, several studies indicate a correlation between GLUT alterations and the development of AD pathologies. However, these findings are not consistent between studies or the different models investigated, which makes it difficult to draw any general conclusions regarding the expression of GLUTs in transgenic AD mouse models. Some of the variation can probably be explained by differences between the models used. However, inconsistent observations are also found within the same model, which could be due to differences in the methods used for analysis. The higher subjectivity and variability of quantitative immunohistochemistry and Western Blots, commonly used for protein quantification in most of the studies performed, could contribute to these discrepancies when compared to more precise methods for protein quantification like ELISA and LC-MS/MS [\u003cspan citationid=\"CR119\" class=\"CitationRef\"\u003e119\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eGLUT alterations in non-transgenic mouse models based on aluminum chloride\u003c/h2\u003e\u003cp\u003eTwo studies examined the protein expression of GLUTs in a non-transgenic AD model based on aluminum chloride administration, which has previously been linked to neurodegeneration in AD [\u003cspan citationid=\"CR157\" class=\"CitationRef\"\u003e157\u003c/span\u003e]. In this model, aluminum chloride administration leads to the development of oxidative stress, neuroinflammation, Aβ accumulation, and cognitive impairment [\u003cspan additionalcitationids=\"CR159\" citationid=\"CR158\" class=\"CitationRef\"\u003e158\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR160\" class=\"CitationRef\"\u003e160\u003c/span\u003e]. Cuciniello et al. found reduced cortical GLUT1 protein levels, unchanged GLUT3, and increased GLUT4 protein levels in mice treated with 100 mg/kg added to the drinking water for 5 weeks when analyzed with Western Blot [\u003cspan citationid=\"CR161\" class=\"CitationRef\"\u003e161\u003c/span\u003e]. In a different study, Yang et al. found reduced GLUT1 and GLUT3 protein levels by Western Blot analysis of brain homogenates in an obesity-related AD model receiving 50 mg/kg aluminum chloride and 120mg/kg D-galactose combined with a high-fat diet for 24 weeks [\u003cspan citationid=\"CR158\" class=\"CitationRef\"\u003e158\u003c/span\u003e]. Both studies demonstrated AD-related pathologies simultaneously with an altered expression of GLUTs. Based on these studies, it was not possible to draw any conclusions regarding the correlation between AD pathology and the expression of GLUTs or whether one influences the other. However, while both studies demonstrate the development of neuroinflammation and neuronal damage and morphological changes, only the study by Yang et al. demonstrates Aβ accumulation, cognitive impairment, and increased concentrations of phosphorylated tau protein, characteristic of AD. Combined with the fact that Cuciniello et al. only observed a reduction in GLUT1 and not GLUT3, this could indicate that the model employed by Yang et al., which includes an extended treatment duration and combination of aluminum chloride, D-galactose, and high-fat diet, might better represent the situation in AD patients. However, this cannot be definitively concluded as it remains to be investigated whether the aluminum chloride model utilized by Cuciniello exhibits the same pathological features.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eOverview of glucose transporter alterations found in mouse studies. WB: Western Blot, IHC: immunohistochemistry. *For non-transgenic models, the treatment duration in adult mice is listed instead of the animal age.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"14\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eModel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ePathology\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eAnalysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c14\" namest=\"c11\"\u003e\u003cp\u003eGLUT alterations\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eName\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eMutations\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eAge\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eAβ\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eTau\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eRegion\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003eMethod\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cem\u003en-values\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cem\u003eGLUT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cem\u003eGLUT2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cem\u003eGLUT3\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cem\u003eGLUT4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGil-Iturbe et al. 2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTg2576 and APPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4\u0026ndash;7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKouznetsova et al. 2006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTg2576\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u0026ndash;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKuznetsova et al. 2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTg2576\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u0026ndash;18 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e- and +\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u0026ndash;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced (18 months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWinkler et al. 2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTg2576\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u0026ndash;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCho et al. 2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNSE/APPsw\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUm et al. 2008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNSE/APPsw\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMerlini et al 2011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArcAb mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9\u0026ndash;13 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC and WB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eShang et al. 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP23 mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e10\u0026ndash;12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHede et al. 2025*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTg-SwDI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eqPCR, ELISA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHuang et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2, 4, and 9 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e- and +\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced (4\u0026ndash;9 months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZerbi et al. 2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 and 12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e- and +\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7\u0026ndash;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHoojimans et al. 2007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8\u0026ndash;18 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced (18 months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKhandewal et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eq-PCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechlovich et al. 2014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMa et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWang et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2, 4, and 9 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e- and +\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced (4\u0026ndash;9 months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhang et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChen et al. 2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGuo et al. 2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPPswe/PS1dE9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHe et al 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1 and APP/PS1- STZ ip (50 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003en.d.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQin et al.2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWu et al. 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC and WB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePang et al. 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWang et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB, qPCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQi et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 and 14 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale and Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHypothalamus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eqPCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIncreased (Young male, old female)\u003c/p\u003e\u003cp\u003eUnaltered (Old male, young female)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePuris et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale +\u003c/p\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLC-MS/MS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAhn et al. 2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4,5 and 9 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC and WB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5 (IHC)\u003c/p\u003e\u003cp\u003e3 (WB)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKim et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u0026ndash;6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNam et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6\u0026ndash;11 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHede et al. 2025*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eqPCR, ELISA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced (gene), Unaltered (protein)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChen et al. 2014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3xTg mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1, MAPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDo et al. 2014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3xTg mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1, MAPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCapillaries\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4\u0026ndash;6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLi et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3xTg mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1, MAPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYan et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3xTg mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1, MAPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4\u0026ndash;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHendrix et al. 2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBRI2-Aβ42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ehAβ42 over-expression\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSimpleWes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhang et al. 2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eP301S mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMAPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLee et al. 2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNSE/hPS2m Tg mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePSEN2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMembrane fractions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJanssen et al. 2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eApoE4-knockin and knockout\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eApoE4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIHC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCuciniello et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAICI\u003csub\u003e3\u003c/sub\u003e AD model (7.7 or 100 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eIncreased\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYang et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAICI3 (50 mg/kg), D-galactose (120 mg/kg), and high-fat diet\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eTransgenic and non-transgenic rat models\u003c/h2\u003e\u003cp\u003eThe rat studies examining GLUT expression mainly included non-transgenic models based on the administration of STZ or aluminum chloride (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Six studies were performed in a sporadic AD model based on single intracerebroventricular injections of 1\u0026ndash;4 mg/kg STZ. Injecting STZ into the ventricles of rats leads to the development of cognitive impairment [\u003cspan citationid=\"CR162\" class=\"CitationRef\"\u003e162\u003c/span\u003e, \u003cspan citationid=\"CR163\" class=\"CitationRef\"\u003e163\u003c/span\u003e] and neuropathology similar to what is observed in sporadic AD patients, including Aβ accumulations in capillaries and neurons, leading to plaque-like formations [\u003cspan additionalcitationids=\"CR164\" citationid=\"CR163\" class=\"CitationRef\"\u003e163\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR165\" class=\"CitationRef\"\u003e165\u003c/span\u003e] tau hyperphosphorylation and preliminary neurofibrillary tangles [\u003cspan citationid=\"CR163\" class=\"CitationRef\"\u003e163\u003c/span\u003e, \u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e, \u003cspan citationid=\"CR167\" class=\"CitationRef\"\u003e167\u003c/span\u003e], neuroinflammation (Biasibetti et al., 2017; Kraska et al., 2012; Prickaerts et al., 1999), and neurodegeneration [\u003cspan citationid=\"CR171\" class=\"CitationRef\"\u003e171\u003c/span\u003e]. These studies demonstrated a decreased GLUT1 [\u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e, \u003cspan citationid=\"CR171\" class=\"CitationRef\"\u003e171\u003c/span\u003e, \u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e] and GLUT3 [\u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e, \u003cspan additionalcitationids=\"CR172\" citationid=\"CR171\" class=\"CitationRef\"\u003e171\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR173\" class=\"CitationRef\"\u003e173\u003c/span\u003e] protein expression both in the cortex and hippocampus of STZ-induced rats compared to wild-type controls when analyzed with Western Blotting. Moreover, Knezovic et al. found an increased GLUT2 protein expression in the hippocampus, but not in the cortex of STZ AD rats, compared to controls. Sajadi et al. analyzed the gene expression of GLUTs and found a decreased expression of both \u003cem\u003eGlut1, Glut3\u003c/em\u003e, and \u003cem\u003eGlut4\u003c/em\u003e in the hippocampus of STZ AD rats, consistent with the findings from studies analyzing the protein levels. Further, two studies demonstrated reduced \u003cem\u003eGlut1\u003c/em\u003e and \u003cem\u003eGlut3\u003c/em\u003e gene expression [\u003cspan citationid=\"CR174\" class=\"CitationRef\"\u003e174\u003c/span\u003e] and decreased hippocampal GLUT4 protein [\u003cspan citationid=\"CR175\" class=\"CitationRef\"\u003e175\u003c/span\u003e] in AD rat models induced by daily intraperitoneal injections of 70 mg/kg or 50 mg/kg aluminum chloride, respectively. Consistently, Radfar et al. demonstrated reduced GLUT4 gene and protein expression in the hypothalamus in an AD rat model induced by intracerebroventricular injections of 10 \u0026micro;g Aβ\u003csub\u003e25\u0026minus;35\u003c/sub\u003e peptide per animal [\u003cspan citationid=\"CR176\" class=\"CitationRef\"\u003e176\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePuris et al. and Ma et al. examined the GLUT1 protein expression in the cortex of transgenic TgF344 rats by LC-MS/MS and APP\u0026thinsp;+\u0026thinsp;PS1 rats by Western Blot, respectively [\u003cspan citationid=\"CR177\" class=\"CitationRef\"\u003e177\u003c/span\u003e, \u003cspan citationid=\"CR178\" class=\"CitationRef\"\u003e178\u003c/span\u003e]. Both transgenic rat models express mutated human transgenes for APP and PSEN1. TgF344 rats contain the human APP transgene with the Swedish mutation and PSEN1 lacking exon 9, similar to the APP/PS1dE9 mouse model, and develop plaques, gliosis, and cognitive impairment at 6 months of age followed by neurofibrillary tangles and neuronal loss at 15 months of age [\u003cspan citationid=\"CR179\" class=\"CitationRef\"\u003e179\u003c/span\u003e], while APP\u0026thinsp;+\u0026thinsp;PS1 rats contain human APP bearing the Swedish and Indiana mutations and PSEN1 with the L166P mutation and develop cognitive impairment and increased Aβ protein load at 10 months of age followed by Aβ plaques and neuronal loss from 18 months of age [\u003cspan citationid=\"CR177\" class=\"CitationRef\"\u003e177\u003c/span\u003e, \u003cspan citationid=\"CR180\" class=\"CitationRef\"\u003e180\u003c/span\u003e, \u003cspan citationid=\"CR181\" class=\"CitationRef\"\u003e181\u003c/span\u003e]. While Ma et al. found an AD-related GLUT1 reduction in 16-month-old APP\u0026thinsp;+\u0026thinsp;PS1 rats by Western Blot, Puris et al. found unaltered GLUT1 expression in 10-month-old TgF344 rats. At 16 months of age, the APP\u0026thinsp;+\u0026thinsp;PS1 model used by Ma et al. has developed cognitive impairment and increased Aβ protein load and the 10-month-old TgF344 rat model used by Puris et al. has developed Aβ plaques, gliosis, and cognitive impairment at this age. Hence, the different results in AD-related GLUT1 expressions do not correlate with differences in the development of disease pathologies between the two models used. However, Ma et al. quantified the GLUT1 protein expression by Western Blot, while Puris et al. used an LC-MS/MS-based approach to analyze the protein concentrations in the membrane fraction of cortical tissue [\u003cspan citationid=\"CR177\" class=\"CitationRef\"\u003e177\u003c/span\u003e, \u003cspan citationid=\"CR178\" class=\"CitationRef\"\u003e178\u003c/span\u003e]. Thus, the inconsistency could be related to the different methods used and differences between examining only the membrane fraction and all tissue components, though this should theoretically not influence the results, as GLUT1 is a transmembrane protein. Moreover, the LC-MS/MS cannot differentiate between the 55 kDa endothelial GLUT1 and the 45 kDa astrocytic GLUT1, whereas Western Blot can separate them based on size differences. Different alterations of the two GLUT1 isoforms were observed in mice by Hendrix et al., who demonstrated a reduction in astrocytic GLUT1, but unaltered membrane-associated GLUT1 in BRI2-Aβ42 mice when analyzed by Western Blot [\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]. Ma et al. do not note whether the GLUT1 concentrations were quantified based on one isoform or both. Alternatively, the inconsistency could simply be related to differences between the two models, which are based on different mutations in the APP and PSEN1 genes.\u003c/p\u003e\u003cp\u003eNevertheless, the results from rat studies demonstrate an AD-related decrease in GLUT1 and GLUT3 expression that is more consistent across models than the observations from mouse studies, and which is similar to that found in human studies. However, the number of rat studies and variation in models used is also lower compared to the mouse studies of GLUT alteration in AD. GLUT2 expression was only analyzed in a single rat study, showing an AD-related increase, which was also consistent with the findings from the one human study examining GLUT2, while two studies consistently found reduced AD-related GLUT4 expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eOverview of glucose transporter alterations found in rat studies. WB: Western Blot, IHC: immunohistochemistry. *For non-transgenic models, the treatment duration in adult rats is listed instead of the animal age.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"14\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eModel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ePathology\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e\u003cp\u003eAnalysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c14\" namest=\"c11\"\u003e\u003cp\u003eGLUT alterations\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eName\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eMutations\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eAge\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eAβ\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eTau\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eRegion\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003eMethod\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cem\u003en-values\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e\u003cem\u003eGLUT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e\u003cem\u003eGLUT2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e\u003cem\u003eGLUT3\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e\u003cem\u003eGLUT4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMa et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP\u0026thinsp;+\u0026thinsp;PS1 rats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePuris et al. 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTgF344-AD rats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAPP, PSEN1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u0026ndash;11 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLC-MS/MS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eNo difference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBazzari et al. 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAICI3 (50 mg/kg/day i.p.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSamman et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAICI\u003csub\u003e3\u003c/sub\u003e (70 mg/kg/day)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eqPCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRadfar et al. 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAβ25\u0026ndash;35 peptide (10 \u0026micro;g/rat I.C.V.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHypothalamus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eqPCR, ELISA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeng et al. 2009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSTZ icv (3 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKnezovic et al. 2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSTZ icv (1.5 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 hour*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eIncreased (HP)\u003c/p\u003e\u003cp\u003eUnaltered\u003c/p\u003e\u003cp\u003e(CX)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSalkovic-Petrisic et al. 2014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSTZ icv (1 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSajadi et al. 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSTZ icv (4 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eqPCR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBiswas et al. 2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSTZ icv (3 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u0026ndash;3 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e8\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePilipenko et al. 2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSTZ icv (2.7 mg/kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 weeks*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e(+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCortex and hippocampus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e The findings from this systematic review and supplementary analyses of GLUT1 in Tg-SwDI and 5xFAD mice suggest that while there is nearly complete consensus in human studies that GLUT1 and GLUT3 are downregulated in AD and some evidence that GLUT2 is upregulated, the results from mouse studies, which employ a wide variety of different models and analysis methods, are far more inconsistent. In contrast, the results from rat studies, which have primarily employed fewer AD models, appear to more consistently demonstrate AD-related GLUT1 and GLUT3 reductions. Some of the variability may be explained by differences in the sex and brain regions studied and the analysis methods used, including the widespread use of methods associated with lower reliability, such as Western Blotting, and higher subjectivity, such as quantitative immunohistochemistry. However, most human studies with good concordance in their results are based on immunohistochemistry, suggesting that the difference between the results from animal studies is probably also due to the variability between the different models used and the general complexity of modelling a multifactorial disease like AD.\u003c/p\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eThe complexity of modelling Alzheimer\u0026rsquo;s disease\u003c/h2\u003e\u003cp\u003eSeveral studies indicate a correlation between the AD characteristic pathology and changes in GLUT expression. This is particularly true for Aβ plaque development, which forms the basis for most animal models, and several examples of GLUT changes have been reported after the development of Aβ plaques (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These findings suggest that Aβ accumulation may accelerate the GLUT alterations in AD. Moreover, Gil-Iturbe et al. analyzed the effect of direct injections of Aβ\u003csub\u003e1\u0026minus;42\u003c/sub\u003e into the brains of healthy mice, in addition to their analysis of transgene models, which resulted in reductions in GLUT1 and GLUT3 protein levels and increased GLUT12 levels similar to observations in the transgene models [\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e], implying that Aβ directly impacts GLUT expression. However, the study by Winkler et al. shows that GLUT1 reduction can accelerate Aβ pathology [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e], potentially by affecting Aβ clearance from the brain through transcriptional inhibition of low-density lipoprotein receptor-related protein 1 (LRP1) [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR182\" class=\"CitationRef\"\u003e182\u003c/span\u003e]. This raises the question about what comes first in sporadic AD where the disease is not initiated by direct mutations in genes related to Aβ accumulation, as is the case in most of the animal studies included in this review. Some studies demonstrate unchanged GLUT expression in transgenic models after the development of Aβ plaques, which argues against Aβ accumulation itself initiating the GLUT changes [\u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e, \u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan citationid=\"CR161\" class=\"CitationRef\"\u003e161\u003c/span\u003e, \u003cspan citationid=\"CR183\" class=\"CitationRef\"\u003e183\u003c/span\u003e]. At the same time, FDG-PET studies report reduced glucose transport long before the development of clinical AD symptoms in patients at increased risk of AD [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGLUT alterations observed in AD have been suggested to be linked to increased tau phosphorylation (Y. Liu et al., 2009). This could indicate that animal models with induced tauopathy would replicate this part of the AD pathology more accurately, which is supported by altered GLUT expressions in nine of the ten studies with induced tauopathy included in this review [\u003cspan citationid=\"CR149\" class=\"CitationRef\"\u003e149\u003c/span\u003e, \u003cspan citationid=\"CR150\" class=\"CitationRef\"\u003e150\u003c/span\u003e, \u003cspan citationid=\"CR158\" class=\"CitationRef\"\u003e158\u003c/span\u003e, \u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e, \u003cspan citationid=\"CR171\" class=\"CitationRef\"\u003e171\u003c/span\u003e, \u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e, \u003cspan additionalcitationids=\"CR184 CR185\" citationid=\"CR183\" class=\"CitationRef\"\u003e183\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR186\" class=\"CitationRef\"\u003e186\u003c/span\u003e]. However, GLUT alterations are also prevalent in several animal models without tauopathy as shown in Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Moreover, studies suggest that the correlation between tauopathy and altered GLUT expression can be explained through decreased levels of tau O-linked N-acetylglucosaminylation (O-GlcNAcylation), which is a distinct type of O-glycosylation within neurons that serves as a sensor of glucose metabolism and regulates intracellular protein phosphorylation [\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e, \u003cspan citationid=\"CR187\" class=\"CitationRef\"\u003e187\u003c/span\u003e]. The protein O-GlcNAcylation levels correlate with the levels of GLUT1 and GLUT3 proteins through positive linear correlation, indicating that the decreased GLUT1 and GLUT3 expressions in AD lead to decreased protein O-GlcNAcylation levels [\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e]. Additionally, O-GlcNAcylation has been shown to inversely regulate tau phosphorylation [\u003cspan citationid=\"CR188\" class=\"CitationRef\"\u003e188\u003c/span\u003e]. Hence, it is suggested that tau hyperphosphorylation may be caused by decreased tau O-GlcNAcylation, induced by decreased brain glucose uptake in AD [\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e, \u003cspan citationid=\"CR187\" class=\"CitationRef\"\u003e187\u003c/span\u003e, \u003cspan citationid=\"CR188\" class=\"CitationRef\"\u003e188\u003c/span\u003e]. Tauopathy therefore, appears to be a consequence, rather than the cause, of decreased glucose uptake resulting from decreased GLUT1 and GLUT3 expression.\u003c/p\u003e\u003cp\u003eSeveral studies have proposed that alterations in brain glucose uptake may serve as an initiating factor for both Aβ accumulation and tau hyperphosphorylation in sporadic AD. This hypothesis is supported by findings from studies employing sporadic AD models, which consistently demonstrate reductions in GLUT1, GLUT3, and GLUT4 expression and an upregulation of GLUT2, which mirrors observations from human studies [\u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e, \u003cspan additionalcitationids=\"CR172 CR173 CR174\" citationid=\"CR171\" class=\"CitationRef\"\u003e171\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR175\" class=\"CitationRef\"\u003e175\u003c/span\u003e, \u003cspan citationid=\"CR184\" class=\"CitationRef\"\u003e184\u003c/span\u003e, \u003cspan citationid=\"CR186\" class=\"CitationRef\"\u003e186\u003c/span\u003e]. Additionally, this interpretation is further supported by previously described findings of reduced glucose uptake preceding the development of clinical symptoms in AD. These findings raise questions about the extent to which transgenic models based on mutations associated with familial AD adequately replicate the sporadic AD scenario, particularly concerning changes in glucose metabolism and GLUT expression. Nonetheless, alterations in GLUTs are also observed in many studies conducted in transgenic animals harboring mutations linked to familial AD.\u003c/p\u003e\u003cp\u003eUnfortunately, due to the significant variability in pathology, age, brain regions, and methodologies employed, it is challenging to draw definitive conclusions regarding the GLUT alterations in AD animal models based on existing studies. To gain a clearer understanding of GLUT alterations in animal models, future studies should strive for better standardization of these factors. Additionally, tracer studies, such as FDG-PET, could potentially provide a more comprehensive picture of glucose metabolism changes. Tracer study results were not included in this review as they reflect glucose uptake rather than direct expression of glucose transport proteins, which was the primary focus. However, they were addressed in a previous review by Kyrtata et al., which found no significant variations in FDG-PET results across different AD animal models [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. This observation was, however, only based on three studies.\u003c/p\u003e\u003cp\u003e While a wide range of animal models can serve as valuable tools for investigating various aspects of AD, careful model selection becomes crucial when evaluating potential new therapies for sporadic AD. This is essential to enhance the translational value of such research and increase the likelihood of successful clinical applications [\u003cspan citationid=\"CR189\" class=\"CitationRef\"\u003e189\u003c/span\u003e, \u003cspan citationid=\"CR190\" class=\"CitationRef\"\u003e190\u003c/span\u003e]. Transgenic AD models offer the advantage of exploring diverse facets of the disease, allowing researchers to delve into specific genetic and molecular underpinnings. However, these models may not fully capture the complex interplay of factors that contribute to sporadic AD, which accounts for most AD cases. According to the results of the present review, the STZ rat model, on the other hand, stands out for its potential to better replicate disturbances in glucose metabolism, as evidenced by the consistent alterations in GLUT expression observed across all studies employing this model. The focus on glucose metabolism in this model also aligns with the growing recognition of its central role in AD pathogenesis. Nonetheless, the generalizability of the STZ model is challenged by the fact that it is based on the administration of a neurotoxin to induce AD pathology, which deviates from the natural development of the disease in humans.\u003c/p\u003e\u003cp\u003eTo effectively advance sporadic AD drug discovery, a balanced approach to model selection is imperative. Researchers should carefully consider the specific research question and the potential therapeutic target before choosing the most appropriate model. In addition, incorporating multiple models could be considered for future research as it can provide a more comprehensive understanding of the disease and its potential therapeutic targets and minimize the chance of making conclusions based on model-specific mechanisms, which do not correlate with the situation in AD patients.\u003c/p\u003e\u003cp\u003eUltimately, the goal is to identify models that strike a balance between capturing the complexity of sporadic AD and providing a robust platform for evaluating novel therapeutic strategies, which remains challenging as the etiology of sporadic AD remains unknown. However, by carefully considering the strengths and limitations of each model, the likelihood of translating preclinical findings into successful clinical applications can be increased.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eCorrelation between alterations in brain GLUTs and insulin signaling\u003c/h2\u003e\u003cp\u003eMultiple studies have established a correlation between brain insulin resistance and altered brain BLUT expression [\u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e, \u003cspan additionalcitationids=\"CR192 CR193 CR194 CR195\" citationid=\"CR191\" class=\"CitationRef\"\u003e191\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR196\" class=\"CitationRef\"\u003e196\u003c/span\u003e]. This observation aligns with the consistent findings of GLUT dysregulation in the STZ AD models reviewed here. STZ is a glucosamine-nitrosourea compound, commonly employed to induce peripheral diabetes in animal models due to its selective toxicity toward insulin-producing cells [\u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e]. Conversely, intracerebroventricular administration of low-dose STZ has been shown to elicit AD-like neuropathological changes rather than systemic diabetes [\u003cspan citationid=\"CR191\" class=\"CitationRef\"\u003e191\u003c/span\u003e, \u003cspan citationid=\"CR197\" class=\"CitationRef\"\u003e197\u003c/span\u003e, \u003cspan citationid=\"CR198\" class=\"CitationRef\"\u003e198\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWithin the brain, insulin receptor activation triggers the phosphorylation and activation of PI3K, subsequently leading to the phosphorylation and activation of protein kinase B (Akt/PKB), which is crucial for the translocation of the insulin-dependent GLUT4 transporter to the cell membrane [\u003cspan citationid=\"CR199\" class=\"CitationRef\"\u003e199\u003c/span\u003e]. In addition, Akt/PKB plays an important role in regulating glucose metabolism and thereby ATP generation, insulin-degrading enzyme (IDE) activity, and glycogen synthase kinase-3 (GSK-3) phosphorylation [\u003cspan citationid=\"CR192\" class=\"CitationRef\"\u003e192\u003c/span\u003e]. Consequently, impaired insulin receptor signaling and reduced Akt/PKB activity contribute to diminished glucose metabolism, ATP depletion, and oxidative stress. Moreover, this may include dysregulation of IDE, due to its PI3-K-dependent regulation [\u003cspan citationid=\"CR200\" class=\"CitationRef\"\u003e200\u003c/span\u003e], which has been linked to the development of sporadic AD [\u003cspan citationid=\"CR201\" class=\"CitationRef\"\u003e201\u003c/span\u003e]. Furthermore, reduced Akt/PKB-mediated GSK-3 inhibition is associated with intracellular Aβ accumulation and tau hyperphosphorylation. Moreover, the inhibition of the PI3K pathway is responsible for regulating hypoxia-inducible factor 1, which activates the transcription of \u003cem\u003eGlut1\u003c/em\u003e and \u003cem\u003eGlut3\u003c/em\u003e [\u003cspan citationid=\"CR202\" class=\"CitationRef\"\u003e202\u003c/span\u003e, \u003cspan citationid=\"CR203\" class=\"CitationRef\"\u003e203\u003c/span\u003e]. When HIF-1 levels decline, GLUT1 and GLUT3 are downregulated, leading to glucose hypometabolism and reduced O-GlcNAcylation, inversely correlating with tau phosphorylation, as described above [\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e, \u003cspan citationid=\"CR187\" class=\"CitationRef\"\u003e187\u003c/span\u003e, \u003cspan citationid=\"CR188\" class=\"CitationRef\"\u003e188\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe results of this review revealed relatively few studies examining GLUT4 expression in AD and inconsistent results were reported as expression levels were shown to increase [\u003cspan citationid=\"CR131\" class=\"CitationRef\"\u003e131\u003c/span\u003e, \u003cspan citationid=\"CR161\" class=\"CitationRef\"\u003e161\u003c/span\u003e], decrease [\u003cspan citationid=\"CR138\" class=\"CitationRef\"\u003e138\u003c/span\u003e, \u003cspan citationid=\"CR149\" class=\"CitationRef\"\u003e149\u003c/span\u003e, \u003cspan citationid=\"CR175\" class=\"CitationRef\"\u003e175\u003c/span\u003e, \u003cspan citationid=\"CR183\" class=\"CitationRef\"\u003e183\u003c/span\u003e, \u003cspan citationid=\"CR186\" class=\"CitationRef\"\u003e186\u003c/span\u003e] and remain unchanged [\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR153\" class=\"CitationRef\"\u003e153\u003c/span\u003e]. Nevertheless, alterations in GLUT expression and insulin resistance have been shown to play a role in the development of AD pathology in humans. Mullins et al. investigated the relationship between insulin resistance-related genes and AD pathologies through 3D spatial maps based on human gene expression and histological data. They found a positive correlation between GLUT4 expression and NFTs, while \u003cem\u003eGlut1\u003c/em\u003e gene expression correlated negatively with NFTs, indicating that regions with high GLUT4 expression and relatively low GLUT1 expression are more prone to develop tauopathy [\u003cspan citationid=\"CR204\" class=\"CitationRef\"\u003e204\u003c/span\u003e]. Moreover, Deng et al. demonstrated a decrease in GLUT1 and GLUT3 in the STZ rat model along with decreased insulin signaling, further emphasizing the relationship between GLUT expression and insulin signaling [\u003cspan citationid=\"CR166\" class=\"CitationRef\"\u003e166\u003c/span\u003e]. In addition, studies examining potential new therapies demonstrated a correlation between altered insulin signaling and the expression of GLUTs. Chen et al. investigated the mechanistic effects in transgenic APPswe/PS1dE9 mice of traditional Chinese medicine that had shown beneficial clinical effects for treating AD patients [\u003cspan citationid=\"CR127\" class=\"CitationRef\"\u003e127\u003c/span\u003e]. In the APPswe/PS1dE9 mouse, increased levels of PI3K, Akt, and phosphorylated Akt as well as increased GLUT1 and GLUT3 expressions were seen following the treatment, which was associated with improved cognition. Moreover, Li et al. demonstrated increased glucose uptake by FDG-PET, increased GLUT4 expression, and decreased insulin receptor inactivation leading to reduced cognitive decline in 3xTg mice following enhanced GLP1 signaling [\u003cspan citationid=\"CR149\" class=\"CitationRef\"\u003e149\u003c/span\u003e]. Mechlovich et al. examined the effect of an ion chelator in APPswe/PS1dE9 mice and found increased cortical insulin and insulin receptor expression, which led to increased activation of the PI3K pathway and elevated levels of HIF-1 α resulting in increased GLUT1 expression [\u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e]. Finally, Pilipenko et al. uncovered improved cognitive performance and reduced gliosis following the normalization of glucose uptake and metabolism induced by the administration of the antidiabetic drug metformin, which increases insulin sensitivity [\u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e, \u003cspan citationid=\"CR205\" class=\"CitationRef\"\u003e205\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eClinical implications of altered GLUT content in AD\u003c/h2\u003e\u003cp\u003eThe critical role of GLUTs in brain function is supported by studies demonstrating substantial neurodegenerative effects following their deletion in animal models [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e, \u003cspan citationid=\"CR206\" class=\"CitationRef\"\u003e206\u003c/span\u003e]. Muneer et al. demonstrated that methamphetamine-induced GLUT1 depletion in mice resulted in compromised BBB integrity, suggesting a role for GLUTs in maintaining BBB function [\u003cspan citationid=\"CR207\" class=\"CitationRef\"\u003e207\u003c/span\u003e]. The clinical implications of GLUT1 deficiency are evident in human GLUT1 deficiency syndrome, a rare genetic disorder characterized by impaired glucose metabolism. This condition manifests with intellectual disability, movement disorders, and refractory epilepsy [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Impairments in glucose metabolism precede the onset of cognitive decline in AD, as evidenced by alterations in glucose transport observed in both AD and mild cognitive impairment (MCI) (Chen and Zhong, 2013; Mosconi et al., 2013).\u003c/p\u003e\u003cp\u003eWinkler et al. further implicated GLUT1 in AD pathogenesis, showing that GLUT1 deficiency exacerbated Aβ pathology, including reduced LRP1 expression, impaired cerebral blood flow, and accelerated BBB breakdown [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. Moreover, several studies included in this review demonstrated improved AD symptoms and pathology along with restored GLUT expressions following various experimental treatments. Yang et al. were able to reduce Aβ aggregation and tau phosphorylation through the administration of the antioxidant polyphenol resveratrol that has known insulin signaling promoting effects, which increased the level of GLUT expression and antioxidant activity while decreasing the microglial activation in the aluminum chloride-induced sporadic AD mouse model [\u003cspan citationid=\"CR158\" class=\"CitationRef\"\u003e158\u003c/span\u003e]. Additionally, reduced cognitive decline and depressive behavior were observed in APP/PS1 transgenic rats following remote ischemic conditioning, which induced increased expression of GLUT1 and other BBB-related proteins along with a reduction of Aβ toxicity [\u003cspan citationid=\"CR178\" class=\"CitationRef\"\u003e178\u003c/span\u003e]. Sajadi et al. observed improved cognitive performance in STZ sporadic AD rats following over-expression of GLUT1, GLUT3, and GLUT4 induced by co-administration of insulin and cinnamon extract [\u003cspan citationid=\"CR186\" class=\"CitationRef\"\u003e186\u003c/span\u003e]. In a different study, Yan et al. demonstrated improved memory and reduced Aβ accumulation and tau phosphorylation along with increased GLUT1 and GLUT3 levels and insulin signaling following administration of icariin to 3xTg mice [\u003cspan citationid=\"CR148\" class=\"CitationRef\"\u003e148\u003c/span\u003e], which is the bioactive component of Chinese herbal medicine, which has shown several beneficial effects including anti-inflammatory activities, neuroprotection, and promotion of glucose metabolism [\u003cspan citationid=\"CR208\" class=\"CitationRef\"\u003e208\u003c/span\u003e, \u003cspan citationid=\"CR209\" class=\"CitationRef\"\u003e209\u003c/span\u003e]. Finally, Qin et al. demonstrated improvement of Aβ accumulation, neuronal degeneration, hippocampal neuron damage, and cognitive impairments along with improved glucose metabolism and transporter expression in APP/PS1 mice following administration of another traditional Chinese medicine, Shen-Zhi-Ling, which is approved by the Chinese Food and Drug Administration for treatment of mild to moderate AD [\u003cspan citationid=\"CR137\" class=\"CitationRef\"\u003e137\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEven though these findings are all pre-clinical and thereby still need to be confirmed in humans, they collectively emphasize the important role of GLUT expression in AD pathology. The expression of GLUT1 and GLUT3, and insulin-dependent GLUT4 to a minor degree, appears to play a significant role in AD development. This suggests that modulating GLUTs could be a therapeutic strategy to mitigate cognitive decline and delay AD progression.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis updated systematic review demonstrates decreased expression of GLUT1 and GLUT3 in AD patients, consistent with the findings of previous reviews [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. This finding is replicated to some extent in rodent AD models, as 75 % of te studies examining the GLUT expression in rodent AD models also find downregulation of GLUT1 and GLUT3. However, the large variation in animal models of AD and the diversity of analytical methods may contribute to inconsistent findings, making it difficult to draw definitive conclusions. Additionally, several studies suggest a correlation between classical AD pathology and GLUT expression, but it is uncertain whether one leads to the other or vice versa, as the results from animal studies support both possibilities. Nevertheless, our findings suggest that alterations in GLUT expression may contribute to the pathogenesis of AD, highlighting the potential for targeting GLUTs as therapeutic strategies for AD. Further research is needed to elucidate the precise mechanisms underlying the GLUT changes and to explore therapeutic strategies targeting GLUTs, which could be tested in both sporadic models, such as the STZ AD model, where glucose disturbances are seemingly replicated most consistently, and transgenic models, which may more closely mimic the classical AD pathology, to increase translatability. Treatment of AD remains challenged by the fact that the precise cause of disease development remains unknown, which is likely due to the complexity of the disease. Thus, a therapeutic strategy possibly requires a combination therapy targeting multiple aspects of the pathology, including altered glucose uptake.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"449\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eAlzheimer\u0026apos;s disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eAPP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eAmyloid precursor protein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eA\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eAmyloid-\u0026beta;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eBBB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eBlood-brain barrier\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eBCEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eBrain capillary endothelial cell\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eCAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eCerebral amyloid angiopathy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eELISA\u003c/p\u003e\n \u003cp\u003eFDG-PET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eEnzyme-linked immunosorbent assay\u003c/p\u003e\n \u003cp\u003eFluorodeoxyglucose Positron Emission Tomography\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eGLUT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eGlucose transporter\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eLRP1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eLipoprotein receptor-related protein 1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eMAPT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eMicrotubule-associated protein\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eMCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eMild cognitive impairment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eNFT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eNeurofibrillary tangles\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003ePSEN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003ePresenilin 1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003ePSEN2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003ePresenilin 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5991%;\"\u003e\n \u003cp\u003eSTZ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80.4009%;\"\u003e\n \u003cp\u003eStreptozotocin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated and analyzed during this study are included in this published paper. All datasets are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by Fonden til L\u0026aelig;gevidenskabens Fremme, Lundbeck Foundation (Research Initiative on Blood\u0026ndash;Brain Barriers and Drug Delivery Grant no. R155-2013-14113), Alzheimer-Forskningsfonden, and Svend Andersen Fonden.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: EH, AB, TM, MST; Acquisition of data - Systematic Review: EH; Acquisition of data \u0026ndash; Original GLUT1 Data: EH, BA, KAK, MST; Investigation: EH, MST; Writing \u0026ndash; Original Draft: EH; Writing \u0026ndash; Review \u0026amp; Editing: EH, AB, BA, KAK, TM, MST; Visualization: EH; Supervision: AB, TM, MST; Funding Acquisition: EH, TM, MST.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank laboratory technicians Merete Fredsgaard, Hanne Krone Nielsen, and Louise Hvilsh\u0026oslash;j Madsen, Aalborg University, Denmark, for excellent technical assistance during the study.\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOyarzabal A, Marin-Valencia I. Synaptic energy metabolism and neuronal excitability, in sickness and health. J Inherit Metab Dis [Internet]. 2019 [cited 2024 May 24];42:220\u0026ndash;36. Available from: https://pubmed.ncbi.nlm.nih.gov/30734319/\u003c/li\u003e\n\u003cli\u003eEngl E, Attwell D. Non-signalling energy use in the brain. J Physiol [Internet]. 2015 [cited 2024 May 24];593:3417\u0026ndash;29. Available from: https://pubmed.ncbi.nlm.nih.gov/25639777/\u003c/li\u003e\n\u003cli\u003eMergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci [Internet]. 2013 [cited 2024 May 24];36:587\u0026ndash;97. Available from: https://pubmed.ncbi.nlm.nih.gov/23968694/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eAbbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. \u003c/span\u003eStructure and function of the blood\u0026ndash;brain barrier. Neurobiol Dis [Internet]. 2009 [cited 2017 Nov 15];37:13\u0026ndash;25. Available from: https://ac-els-cdn-com.zorac.aub.aau.dk/S0969996109002083/1-s2.0-S0969996109002083-main.pdf?_tid=0f3148b4-c9fb-11e7-81cc-00000aacb35d\u0026amp;acdnat=1510746759_1b4a38d614c08620802aec1760f84e87\u003c/li\u003e\n\u003cli\u003eMisje Mathiisen T, Lehre KP, Christian Danbolt N, Petter Ottersen O. The Perivascular Astroglial Sheath Provides a Complete Covering of the Brain Microvessels: An Electron Microscopic 3D Reconstruction. Glia [Internet]. 2010 [cited 2017 Nov 18];58:1094\u0026ndash;103. Available from: https://synapseweb.clm.utexas.edu/sites/default/files/synapseweb/files/2010gliamathiisenottersentheperivascastrosheath.pdf\u003c/li\u003e\n\u003cli\u003eZlokovic B V. Neurovascular pathways to neurodegeneration in Alzheimer\u0026rsquo;s disease and other disorders. 2011 [cited 2023 Dec 12]; Available from: www.nature.com/reviews/neuro\u003c/li\u003e\n\u003cli\u003eZlokovic B V. The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders. Neuron [Internet]. 2008 [cited 2023 Dec 12];57:178\u0026ndash;201. Available from: http://www.cell.com/article/S0896627308000342/fulltext\u003c/li\u003e\n\u003cli\u003ePatching SG. Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery. Mol Neurobiol. 2017;54:1046\u0026ndash;77.\u003c/li\u003e\n\u003cli\u003eSimpson IA, Carruthers A, Vannucci SJ. Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters. Journal of Cerebral Blood Flow \u0026amp; Metabolism [Internet]. 2007 [cited 2023 Dec 12];27:1766\u0026ndash;91. Available from: https://journals.sagepub.com/doi/10.1038/sj.jcbfm.9600521\u003c/li\u003e\n\u003cli\u003eBouzier-Sore AK, Merle M, Magistretti PJ, Pellerin L. Feeding active neurons: (re)emergence of a nursing role for astrocytes. J Physiol Paris [Internet]. 2002 [cited 2024 May 24];96:273\u0026ndash;82. Available from: https://pubmed.ncbi.nlm.nih.gov/12445906/\u003c/li\u003e\n\u003cli\u003eBentsen MA, Mirzadeh Z, Schwartz MW. Revisiting how the brain senses glucose - and why. Cell Metab [Internet]. 2019 [cited 2024 May 24];29:11. Available from: /pmc/articles/PMC6326855/\u003c/li\u003e\n\u003cli\u003eMaher F, Vannucci SJ, Simpson IA. Glucose transporter proteins in brain. FASEB J [Internet]. 1994 [cited 2024 May 24];8:1003\u0026ndash;11. Available from: https://pubmed.ncbi.nlm.nih.gov/7926364/\u003c/li\u003e\n\u003cli\u003eGandhi GK, Cruz NF, Ball KK, Dienel GA. Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem [Internet]. 2009 [cited 2024 May 24];111:522\u0026ndash;36. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1471-4159.2009.06333.x\u003c/li\u003e\n\u003cli\u003eSpinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol [Internet]. 2018 [cited 2024 May 24];20:745\u0026ndash;54. Available from: https://pubmed.ncbi.nlm.nih.gov/29950572/\u003c/li\u003e\n\u003cli\u003eReiss AB, Gulkarov S, Jacob B, Srivastava A, Pinkhasov A, Gomolin IH, et al. Mitochondria in Alzheimer\u0026rsquo;s Disease Pathogenesis. Life 2024, Vol 14, Page 196 [Internet]. 2024 [cited 2024 May 24];14:196. Available from: https://www.mdpi.com/2075-1729/14/2/196/htm\u003c/li\u003e\n\u003cli\u003eStobart JL, Anderson CM. Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci [Internet]. 2013 [cited 2024 May 22];7. Available from: /pmc/articles/PMC3622037/\u003c/li\u003e\n\u003cli\u003eCunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, et al. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer\u0026rsquo;s Disease. Front Mol Neurosci [Internet]. 2016 [cited 2024 May 22];9. Available from: /pmc/articles/PMC4937039/\u003c/li\u003e\n\u003cli\u003eHenderson ST. High carbohydrate diets and Alzheimer\u0026rsquo;s disease. Med Hypotheses. 2004;62:689\u0026ndash;700.\u003c/li\u003e\n\u003cli\u003eLin AL, Zhang W, Gao X, Watts L. Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain. Neurobiol Aging [Internet]. 2015 [cited 2024 May 24];36:2296. Available from: /pmc/articles/PMC4457572/\u003c/li\u003e\n\u003cli\u003eTakahashi S, Takahashi S. Lactate and Ketone Bodies Act as Energy Substrates as Well as Signal Molecules in the Brain. Psychology and Pathophysiological Outcomes of Eating [Internet]. 2021 [cited 2024 May 24]; Available from: https://www.intechopen.com/chapters/75814\u003c/li\u003e\n\u003cli\u003eCourchesne-Loyer A, Fortier M, Tremblay-Mercier J, Chouinard-Watkins R, Roy M, Nugent S, et al. Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: estimated potential contribution to brain energy metabolism. Nutrition [Internet]. 2013 [cited 2024 Jun 6];29:635\u0026ndash;40. Available from: https://pubmed.ncbi.nlm.nih.gov/23274095/\u003c/li\u003e\n\u003cli\u003eCunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, et al. Brain fuel metabolism, aging, and Alzheimer\u0026rsquo;s disease. Nutrition [Internet]. 2011 [cited 2024 Jun 6];27:3\u0026ndash;20. Available from: https://pubmed.ncbi.nlm.nih.gov/21035308/\u003c/li\u003e\n\u003cli\u003eZahoor I, Rui B, Khan J, Datta I, Giri S. An emerging potential of metabolomics in multiple sclerosis: a comprehensive overview. Cell Mol Life Sci [Internet]. 2021 [cited 2024 May 24];78:3181\u0026ndash;203. Available from: https://pubmed.ncbi.nlm.nih.gov/33449145/\u003c/li\u003e\n\u003cli\u003eTefera TW, Steyn FJ, Ngo ST, Borges K. CNS glucose metabolism in Amyotrophic Lateral Sclerosis: a therapeutic target? Cell \u0026amp; Bioscience 2021 11:1 [Internet]. 2021 [cited 2024 May 24];11:1\u0026ndash;17. Available from: https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00511-2\u003c/li\u003e\n\u003cli\u003eDunn L, Allen GFG, Mamais A, Ling H, Li A, Duberley KE, et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson\u0026rsquo;s disease. Neurobiol Aging [Internet]. 2014 [cited 2024 May 24];35:1111\u0026ndash;5. Available from: https://pubmed.ncbi.nlm.nih.gov/24300239/\u003c/li\u003e\n\u003cli\u003eButterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci [Internet]. 2019 [cited 2024 May 24];20:148\u0026ndash;60. Available from: https://pubmed.ncbi.nlm.nih.gov/30737462/\u003c/li\u003e\n\u003cli\u003eHardy JA, Higgins GA. Alzheimer\u0026rsquo;s disease: The amyloid cascade hypothesis. Science (1979) [Internet]. 1992 [cited 2024 May 24];256:184\u0026ndash;5. Available from: https://www.science.org/doi/10.1126/science.1566067\u003c/li\u003e\n\u003cli\u003eKayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science (1979). 2003;300:486\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eChen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, et al. A learning deficit related to age and \u0026beta;-amyloid plaques in a mouse model of alzheimer\u0026rsquo;s disease. Nature. 2000;408:975\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eGoate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u0026rsquo;s disease. Nature 1991 349:6311 [Internet]. 1991 [cited 2024 May 24];349:704\u0026ndash;6. Available from: https://www.nature.com/articles/349704a0\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eCh\u0026eacute;telat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, et al. \u003c/span\u003eRelationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol [Internet]. 2010 [cited 2024 May 27];67:317\u0026ndash;24. Available from: https://pubmed.ncbi.nlm.nih.gov/20373343/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eGrundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. \u003c/span\u003eAbnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A [Internet]. 1986 [cited 2024 May 27];83:4913\u0026ndash;7. Available from: https://pubmed.ncbi.nlm.nih.gov/3088567/\u003c/li\u003e\n\u003cli\u003eHaass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer\u0026rsquo;s amyloid \u0026beta;-peptide. Nature Reviews Molecular Cell Biology 2007 8:2 [Internet]. 2007 [cited 2024 May 27];8:101\u0026ndash;12. Available from: https://www.nature.com/articles/nrm2101\u003c/li\u003e\n\u003cli\u003eEikelenboom P, Zhan SS, van Gool WA, Allsop D. Inflammatory mechanisms in Alzheimer\u0026rsquo;s disease. Trends Pharmacol Sci. 1994;15:447\u0026ndash;50.\u003c/li\u003e\n\u003cli\u003eMcGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev. 1995;21:195\u0026ndash;218.\u003c/li\u003e\n\u003cli\u003eRogers J, Webster S, Lue LF, Brachova L, Civin WH, Emmerling M, et al. Inflammation and Alzheimer\u0026rsquo;s disease pathogenesis. Neurobiol Aging. 1996;17:681\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eBraak H, Braak E. Morphological criteria for the recognition of Alzheimer\u0026rsquo;s disease and the distribution pattern of cortical changes related to this disorder. Neurobiol Aging. 1994;15:355\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eGlenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer\u0026rsquo;s disease: Their nature and pathogenesis. Appl Pathol. 1984;2:357\u0026ndash;69.\u003c/li\u003e\n\u003cli\u003eChow VW, Mattson MP, Wong PC, Gleichmann M. An Overview of APP Processing Enzymes and Products. Neuromolecular Med [Internet]. 2010 [cited 2024 Jul 26];12:1. Available from: /pmc/articles/PMC2889200/\u003c/li\u003e\n\u003cli\u003eCastello MA, Soriano S. On the origin of Alzheimer\u0026rsquo;s disease. Trials and tribulations of the amyloid hypothesis. Ageing Res Rev [Internet]. 2014 [cited 2024 May 27];13:10\u0026ndash;2. Available from: https://pubmed.ncbi.nlm.nih.gov/24252390/\u003c/li\u003e\n\u003cli\u003eMorris GP, Clark IA, Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer\u0026rsquo;s disease. Acta Neuropathol Commun [Internet]. 2014 [cited 2024 May 27];2. Available from: https://pubmed.ncbi.nlm.nih.gov/25231068/\u003c/li\u003e\n\u003cli\u003eHerrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci [Internet]. 2015 [cited 2024 May 27];18:794\u0026ndash;9. Available from: https://pubmed.ncbi.nlm.nih.gov/26007212/\u003c/li\u003e\n\u003cli\u003eWeglinski C, Jeans A. Amyloid-\u0026beta; in Alzheimer\u0026rsquo;s disease \u0026mdash; front and centre after all? Neuronal Signal [Internet]. 2023 [cited 2024 May 27];7:20220086. Available from: /neuronalsignal/article/7/1/NS20220086/232232/Amyloid-in-Alzheimer-s-disease-front-and-centre\u003c/li\u003e\n\u003cli\u003eMusiek ES, Gomez-Isla T, Holtzman DM. Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside. J Clin Invest [Internet]. 2021 [cited 2024 May 27];131. Available from: https://pubmed.ncbi.nlm.nih.gov/34651585/\u003c/li\u003e\n\u003cli\u003eCH van D, CJ S, P A, RJ B, C C, M G, et al. Lecanemab in Early Alzheimer\u0026rsquo;s Disease. N Engl J Med [Internet]. 2023 [cited 2024 May 27];388:142\u0026ndash;3. Available from: https://pubmed.ncbi.nlm.nih.gov/36449413/\u003c/li\u003e\n\u003cli\u003eBudd Haeberlein S, Aisen PS, Barkhof F, Chalkias S, Chen T, Cohen S, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer\u0026rsquo;s Disease. J Prev Alzheimers Dis [Internet]. 2022 [cited 2024 May 23];9:197\u0026ndash;210. Available from: https://pubmed.ncbi.nlm.nih.gov/35542991/\u003c/li\u003e\n\u003cli\u003eSevigny J, Chiao P, Bussi\u0026egrave;re T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces A\u0026beta; plaques in Alzheimer\u0026rsquo;s disease. Nature [Internet]. 2016 [cited 2024 May 23];537:50\u0026ndash;6. Available from: https://pubmed.ncbi.nlm.nih.gov/27582220/\u003c/li\u003e\n\u003cli\u003eKosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A [Internet]. 1986 [cited 2024 May 27];83:4044\u0026ndash;8. Available from: https://pubmed.ncbi.nlm.nih.gov/2424016/\u003c/li\u003e\n\u003cli\u003eSoeda Y, Takashima A. New Insights Into Drug Discovery Targeting Tau Protein. Front Mol Neurosci. 2020;13:590896.\u003c/li\u003e\n\u003cli\u003eHanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study. JAMA Neurol [Internet]. 2019 [cited 2024 May 27];76:915\u0026ndash;24. Available from: https://pubmed.ncbi.nlm.nih.gov/31157827/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003e51. Landau SM, Mintun MA, Joshi AD, Koeppe RA, Petersen RC, Aisen PS, et al. \u003c/span\u003eAmyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol [Internet]. 2012 [cited 2023 Dec 12];72:578\u0026ndash;86. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ana.23650\u003c/li\u003e\n\u003cli\u003eChen Z, Zhong C. Oxidative stress in Alzheimer\u0026rsquo;s disease. Neurosci Bull [Internet]. 2014 [cited 2024 Jun 6];30:271\u0026ndash;81. Available from: https://pubmed.ncbi.nlm.nih.gov/24664866/\u003c/li\u003e\n\u003cli\u003eBhatia V, Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer\u0026rsquo;s disease. J Neurol Sci. 2021;421.\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eMosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, Li Y, et al. \u003c/span\u003eFDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer\u0026rsquo;s disease. Eur J Nucl Med Mol Imaging [Internet]. 2009 [cited 2023 Dec 12];36:811\u0026ndash;22. Available from: https://link.springer.com/article/10.1007/s00259-008-1039-z\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eMosconi L, Rinne JO, Tsui WH, Murray J, Li Y, Glodzik L, et al. \u003c/span\u003eAmyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer\u0026rsquo;s parents. Neurobiol Aging. 2013;34:22\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eProtas HD, Chen K, Langbaum JBS, Fleisher AS, Alexander GE, Lee W, et al. Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease. JAMA Neurol [Internet]. 2013 [cited 2023 Dec 12];70:320. Available from: /pmc/articles/PMC3745014/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eOu YN, Xu W, Li JQ, Guo Y, Cui M, Chen KL, et al. \u003c/span\u003eFDG-PET as an independent biomarker for Alzheimer\u0026rsquo;s biological diagnosis: A longitudinal study. Alzheimers Res Ther [Internet]. 2019 [cited 2024 May 23];11:1\u0026ndash;11. Available from: https://alzres.biomedcentral.com/articles/10.1186/s13195-019-0512-1\u003c/li\u003e\n\u003cli\u003eBailly M, Destrieux C, Hommet C, Mondon K, Cottier JP, Beaufils E, et al. Precuneus and Cingulate Cortex Atrophy and Hypometabolism in Patients with Alzheimer\u0026rsquo;s Disease and Mild Cognitive Impairment: MRI and 18F-FDG PET Quantitative Analysis Using FreeSurfer. Biomed Res Int [Internet]. 2015 [cited 2024 May 23];2015. Available from: /pmc/articles/PMC4539420/\u003c/li\u003e\n\u003cli\u003eZeller K, Rahner-Welsch S, Kuschinsky W. Distribution of Glut1 glucose transporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. Journal of Cerebral Blood Flow and Metabolism [Internet]. 1997 [cited 2023 Dec 12];17:204\u0026ndash;9. Available from: https://journals.sagepub.com/doi/10.1097/00004647-199702000-00010?url_ver=Z39.88-2003\u0026amp;rfr_id=ori%3Arid%3Acrossref.org\u0026amp;rfr_dat=cr_pub++0pubmed\u003c/li\u003e\n\u003cli\u003eChoeiri C, Staines W, Miki T, Seino S, Messier C. Glucose transporter plasticity during memory processing. Neuroscience [Internet]. 2005 [cited 2023 Dec 12];130:591\u0026ndash;600. Available from: http://www.ibroneuroscience.org/article/S030645220400836X/fulltext\u003c/li\u003e\n\u003cli\u003eAllen A, Messier C. Plastic changes in the astrocyte GLUT1 glucose transporter and beta-tubulin microtubule protein following voluntary exercise in mice. Behavioural Brain Research. 2013;240:95\u0026ndash;102.\u003c/li\u003e\n\u003cli\u003eKyrtata N, Emsley HCA, Sparasci O, Parkes LM, Dickie BR. A Systematic Review of Glucose Transport Alterations in Alzheimer\u0026rsquo;s Disease. Front Neurosci. 2021;15.\u003c/li\u003e\n\u003cli\u003eSzablewski L. Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer\u0026rsquo;s Disease. Int J Mol Sci [Internet]. 2021 [cited 2024 May 21];22:8142. Available from: https://www.mdpi.com/1422-0067/22/15/8142\u003c/li\u003e\n\u003cli\u003eSzablewski L. Glucose Transporters in Brain: In Health and in Alzheimer\u0026rsquo;s Disease. Journal of Alzheimer\u0026rsquo;s Disease [Internet]. 2016 [cited 2024 May 21];55:1307\u0026ndash;20. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress\u0026amp;doi=10.3233/JAD-160841\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eWang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP, et al. \u003c/span\u003eGlut-1 deficiency syndrome: Clinical, genetic, and therapeutic aspects. Ann Neurol [Internet]. 2005 [cited 2021 Jan 20];57:111\u0026ndash;8. Available from: http://doi.wiley.com/10.1002/ana.20331\u003c/li\u003e\n\u003cli\u003eKlepper J, Akman C, Armeno M, Auvin S, Cervenka M, Cross HJ, et al. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open [Internet]. 2020 [cited 2022 Sep 8];5:354\u0026ndash;65. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/epi4.12414\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eBen-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, et al. \u003c/span\u003eMfsd2a is critical for the formation and function of the blood-brain barrier. Nature. 2014;509:507\u0026ndash;11.\u003c/li\u003e\n\u003cli\u003eZhao Z, Zlokovic B V. Blood-Brain Barrier: A Dual Life of MFSD2A? Neuron [Internet]. 2014 [cited 2023 Dec 12];82:728. Available from: /pmc/articles/PMC4114515/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eZheng PP, Romme E, Van Der Spek PJ, Dirven CMF, Willemsen R, Kros JM. \u003c/span\u003eGlut1/SLC2A1 is crucial for the development of the blood-brain barrier in vivo. Ann Neurol [Internet]. 2010 [cited 2023 Dec 12];68:835\u0026ndash;44. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ana.22318\u003c/li\u003e\n\u003cli\u003eWinkler EA, Nishida Y, Sagare AP, Rege S V, Bell RD, Perlmutter D, et al. GLUT1 reductions exacerbate Alzheimer\u0026rsquo;s disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci [Internet]. 2015;18:521\u0026ndash;30. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L602680501\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eNiccoli T, Cabecinha M, Tillmann A, Kerr F, Wong CT, Cardenes D, et al. Increased Glucose Transport into Neurons Rescues A\u0026beta; Toxicity in Drosophila. Current Biology [Internet]. 2016 [cited 2023 Nov 3];26:2291. Available from: /pmc/articles/PMC5026704/\u003c/li\u003e\n\u003cli\u003eRaut S, Bhalerao A, Powers M, Gonzalez M, Mancuso S, Cucullo L. Hypometabolism, Alzheimer\u0026rsquo;s Disease, and Possible Therapeutic Targets: An Overview. Cells [Internet]. 2023 [cited 2024 May 22];12. Available from: /pmc/articles/PMC10453773/\u003c/li\u003e\n\u003cli\u003eHuang X, Qi J, Su Y, Zhou Y, Wang Q, Huang T, et al. Endothelial DR6 in blood-brain barrier malfunction in Alzheimer\u0026rsquo;s disease. Cell Death Dis [Internet]. 2024;15. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2029404815\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eGil-Iturbe E, Solas M, Cuadrado-Tejedo M, Garc\u0026iacute;a-Osta A, Escot\u0026eacute; X, Ram\u0026iacute;rez MJ, et al. GLUT12 Expression in Brain of Mouse Models of Alzheimer\u0026rsquo;s Disease. Mol Neurobiol [Internet]. 2020 [cited 2024 May 21];57:798\u0026ndash;805. Available from: https://link.springer.com/10.1007/s12035-019-01743-1\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eAhn K-C, Learman CR, Dunbar GL, Maiti P, Jang W-C, Cha H-C, et al. \u003c/span\u003eCharacterization of Impaired Cerebrovascular Structure in APP/PS1 Mouse Brains. Neuroscience [Internet]. 2018;385:246\u0026ndash;54. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2000796072\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eKuznetsova E, Schliebs R. \u0026beta;Amyloid, cholinergic transmission, and cerebrovascular system - a developmental study in a mouse model of alzheimer\u0026rsquo;s disease. Curr Pharm Des [Internet]. 2013;19:6749\u0026ndash;65. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L605249728\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eHe C, Li Q, Cui Y, Gao P, Shu W, Zhou Q, et al. Recurrent moderate hypoglycemia accelerates the progression of Alzheimer\u0026rsquo;s disease through impairment of the TRPC6/GLUT3 pathway. JCI Insight [Internet]. 2022 [cited 2024 May 21];7. Available from: https://insight.jci.org/articles/view/154595\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eJanssen CIF, Jansen D, Mutsaers MPC, Dederen PJWC, Geenen B, Mulder MT, et al. \u003c/span\u003eThe Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice. Schulz C, editor. PLoS One [Internet]. 2016 [cited 2024 May 21];11:e0155307. Available from: https://dx.plos.org/10.1371/journal.pone.0155307\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eHendrix RD, Ou Y, Davis JE, Odle AK, Groves TR, Allen AR, et al. \u003c/span\u003eAlzheimer amyloid-\u0026beta;- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood. Neurobiol Aging [Internet]. 2021 [cited 2024 May 21];97:73\u0026ndash;88. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0197458020303109\u003c/li\u003e\n\u003cli\u003eChen Y, Zhao Y, Dai C-L, Liang Z, Run X, Iqbal K, et al. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces A\u0026beta; level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol [Internet]. 2014;261:610\u0026ndash;9. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L373855009\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. \u003c/span\u003eThe PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 [cited 2024 Jun 8];372. Available from: https://www.bmj.com/content/372/bmj.n71\u003c/li\u003e\n\u003cli\u003eLivak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2 C T Method. METHODS. 2001;25:402\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eZhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O\u0026rsquo;Keeffe S, et al. An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. Journal of Neuroscience [Internet]. 2014 [cited 2024 Jul 18];34:11929\u0026ndash;47. Available from: https://www.jneurosci.org/content/34/36/11929\u003c/li\u003e\n\u003cli\u003eBurgos M, Gil-Iturbe E, Idoate-Bay\u0026oacute;n A, Castilla-Madrigal R, Moreno-Aliaga MJ, Lostao MP. The glucose transporter GLUT12, a new actor in obesity and cancer. J Physiol Biochem [Internet]. 2024 [cited 2024 Jul 19];1\u0026ndash;11. Available from: https://link.springer.com/article/10.1007/s13105-024-01028-9\u003c/li\u003e\n\u003cli\u003eBurke MJC, Nelson L, Slade JY, Oakley AE, Khundakar AA, Kalaria RN. Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias. Neuropathol Appl Neurobiol [Internet]. 2014;40:284\u0026ndash;95. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L372595495\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eKalaria RN, Harik SI. Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J Neurochem [Internet]. 1989;53:1083\u0026ndash;8. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L19238473\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eHorwood N, Davies DC. Immunolabelling of hippocampal microvessel glucose transporter protein is reduced in Alzheimer\u0026rsquo;s disease. Virchows Archiv [Internet]. 1994;425:69\u0026ndash;72. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L24295508\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eKawai M, Kalaria RN, Harik SI, Perry G. The relationship of amyloid plaques to cerebral capillaries in Alzheimer\u0026rsquo;s disease. American Journal of Pathology [Internet]. 1990;137:1435\u0026ndash;46. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L21046307\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eSimpson IA, Davies P. Reduced glucose transporter concentrations in brains of patients with Alzheimer\u0026rsquo;s disease. Ann Neurol [Internet]. 1994 [cited 2024 May 21];36:800\u0026ndash;1. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ana.410360522\u003c/li\u003e\n\u003cli\u003eHarr SD, Simonian NA, Hyman BT. Functional alterations in Alzheimer\u0026rsquo;s disease: Decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J Neuropathol Exp Neurol [Internet]. 1995;54:38\u0026ndash;41. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L25018569\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eAn Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, et al. \u003c/span\u003eEvidence for brain glucose dysregulation in Alzheimer\u0026rsquo;s disease. Alzheimer\u0026rsquo;s \u0026amp; Dementia [Internet]. 2018 [cited 2024 May 21];14:318\u0026ndash;29. Available from: https://alz-journals.onlinelibrary.wiley.com/doi/10.1016/j.jalz.2017.09.011\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eWang Q, Huang X, Su Y, Yin G, Wang S, Yu B, et al. \u003c/span\u003eActivation of Wnt/\u0026beta;-catenin pathway mitigates blood\u0026ndash;brain barrier dysfunction in Alzheimer\u0026rsquo;s disease. Brain [Internet]. 2022 [cited 2024 May 21];145:4474\u0026ndash;88. Available from: https://academic.oup.com/brain/article/145/12/4474/6630034\u003c/li\u003e\n\u003cli\u003eLeclerc M, Tremblay C, Bourassa P, Schneider JA, Bennett DA, Calon F. Lower GLUT1 and unchanged MCT1 in Alzheimer\u0026rsquo;s disease cerebrovasculature. Journal of Cerebral Blood Flow and Metabolism. 2024;\u003c/li\u003e\n\u003cli\u003eMooradian AD, Chung HC, Shah GN. GLUT-1 expression in the cerebra of patients with Alzheimer\u0026rsquo;s disease. Neurobiol Aging [Internet]. 1997;18:469\u0026ndash;74. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L27497142\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eJin N, Qian W, Yin X, Zhang L, Iqbal K, Grundke-Iqbal I, et al. \u003c/span\u003eCREB regulates the expression of neuronal glucose transporter 3: A possible mechanism related to impaired brain glucose uptake in Alzheimer\u0026rsquo;s disease. Nucleic Acids Res [Internet]. 2013;41:3240\u0026ndash;56. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L368759985\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eLiu Y, Liu F, Grundke‐Iqbal I, Iqbal K, Gong C. Brain glucose transporters, \u003cem\u003eO\u003c/em\u003e ‐GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer\u0026rsquo;s disease. J Neurochem [Internet]. 2009 [cited 2024 May 21];111:242\u0026ndash;9. Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.06320.x\u003c/li\u003e\n\u003cli\u003eNam M-H, Ko HY, Kim D, Lee S, Park YM, Hyeon SJ, et al. Visualizing reactive astrocyte-neuron interaction in Alzheimer\u0026rsquo;s disease using 11C-acetate and 18F-FDG. Brain [Internet]. 2023 [cited 2024 May 21];146:2957\u0026ndash;74. Available from: https://academic.oup.com/brain/article/146/7/2957/7117615\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003e98. Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong C-X. \u003c/span\u003eDecreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett [Internet]. 2008;582:359\u0026ndash;64. Available from: https://febs.onlinelibrary.wiley.com/doi/10.1016/j.febslet.2007.12.035\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eKouznetsova E, Klingner M, Sorger D, Sabri O, Gro\u0026szlig;mann U, Steinbach J, et al. \u003c/span\u003eDevelopmental and amyloid plaque‐related changes in cerebral cortical capillaries in transgenic Tg2576 Alzheimer mice. International Journal of Developmental Neuroscience [Internet]. 2006 [cited 2024 May 21];24:187\u0026ndash;93. Available from: https://onlinelibrary.wiley.com/doi/10.1016/j.ijdevneu.2005.11.011\u003c/li\u003e\n\u003cli\u003eHsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science [Internet]. 1996 [cited 2024 Jun 17];274:99\u0026ndash;102. Available from: https://pubmed.ncbi.nlm.nih.gov/8810256/\u003c/li\u003e\n\u003cli\u003eFrautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol [Internet]. 1998 [cited 2024 Jul 19];152:307. Available from: /pmc/articles/PMC1858113/?report=abstract\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eUm HS, Kang EB, Leem YH, Cho IH, Yang CH, Chae KR, et al. \u003c/span\u003eExercise training acts as a therapeutic strategy for reduction of the pathogenic phonetypes for Alzheimer\u0026rsquo;s disease in an NSE/APPSw-transgenic model. Int J Mol Med [Internet]. 2008 [cited 2024 May 21];22:529\u0026ndash;39. Available from: http://www.spandidos-publications.com/10.3892/ijmm_00000052/abstract\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eCho JY, Um HS, Kang EB, Cho IH, Kim CH, Cho JS, et al. \u003c/span\u003eThe combination of exercise training and \u0026alpha;-lipoic acid treatment has therapeutic effects on the pathogenic phenotypes of Alzheimer\u0026rsquo;s disease in NSE/APPsw-transgenic mice. Int J Mol Med [Internet]. 2010;25:337\u0026ndash;46. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L358316176\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eHwang DY, Cho JS, Lee SH, Chae KR, Lim HJ, Min SH, et al. \u003c/span\u003eAberrant expressions of pathogenic phenotype in Alzheimer\u0026rsquo;s diseased transgenic mice carrying NSE-controlled APPsw. Exp Neurol [Internet]. 2004 [cited 2024 Jun 25];186:20\u0026ndash;32. Available from: https://pubmed.ncbi.nlm.nih.gov/14980807/\u003c/li\u003e\n\u003cli\u003eKim JH, Nam YP, Jeon SM, Han HS, Suk K. Amyloid neurotoxicity is attenuated by metallothionein: dual mechanisms at work. J Neurochem [Internet]. 2012 [cited 2024 Jun 25];121:751\u0026ndash;62. Available from: https://pubmed.ncbi.nlm.nih.gov/22404335/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eShang J, Yamashita T, Tian F, Li X, Liu X, Shi X, et al. \u003c/span\u003eChronic cerebral hypoperfusion alters amyloid-\u0026beta; transport related proteins in the cortical blood vessels of Alzheimer\u0026rsquo;s disease model mouse. Brain Res [Internet]. 2019;1723. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2002702172\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eSturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A [Internet]. 1997 [cited 2024 Jun 25];94:13287\u0026ndash;92. Available from: https://pubmed.ncbi.nlm.nih.gov/9371838/\u003c/li\u003e\n\u003cli\u003eCalhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, et al. Neuron loss in APP transgenic mice. Nature [Internet]. 1998 [cited 2024 Jun 25];395:755\u0026ndash;6. Available from: https://pubmed.ncbi.nlm.nih.gov/9796810/\u003c/li\u003e\n\u003cli\u003eKelly PH, Bondolfi L, Hunziker D, Schlecht HP, Carver K, Maguire E, et al. Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol Aging [Internet]. 2003 [cited 2024 Jun 25];24:365\u0026ndash;78. Available from: https://pubmed.ncbi.nlm.nih.gov/12498971/\u003c/li\u003e\n\u003cli\u003eReichwald J, Danner S, Wiederhold KH, Staufenbiel M. Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation [Internet]. 2009 [cited 2024 Jul 19];6:1\u0026ndash;12. Available from: https://link.springer.com/articles/10.1186/1742-2094-6-35\u003c/li\u003e\n\u003cli\u003eMerlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular \u0026beta;-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcA\u0026beta; mice. Acta Neuropathol [Internet]. 2011 [cited 2024 May 21];122:293\u0026ndash;311. Available from: http://link.springer.com/10.1007/s00401-011-0834-y\u003c/li\u003e\n\u003cli\u003eKnobloch M, Konietzko U, Krebs DC, Nitsch RM. Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging [Internet]. 2007 [cited 2024 Jun 25];28:1297\u0026ndash;306. Available from: https://pubmed.ncbi.nlm.nih.gov/16876915/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eMiao J, Xu F, Davis J, Otte-H\u0026ouml;ller I, Verbeek MM, Van Nostrand WE. \u003c/span\u003eCerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol [Internet]. 2005 [cited 2024 Jun 25];167:505\u0026ndash;15. Available from: https://pubmed.ncbi.nlm.nih.gov/16049335/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eDavis J, Xu F, Deane R, Romanov G, Previti M Lou, Zeigler K, et al. \u003c/span\u003eEarly-onset and Robust Cerebral Microvascular Accumulation of Amyloid \u0026beta;-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid \u0026beta;-Protein Precursor. Journal of Biological Chemistry. 2004;279:20296\u0026ndash;306.\u003c/li\u003e\n\u003cli\u003eSpina S, La Joie R, Petersen C, Nolan AL, Cuevas D, Cosme C, et al. Comorbid neuropathological diagnoses in early versus late-onset Alzheimer\u0026rsquo;s disease. Brain [Internet]. 2021 [cited 2024 Jul 19];144:2186\u0026ndash;98. Available from: https://dx.doi.org/10.1093/brain/awab099\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eToledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. \u003c/span\u003eContribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer\u0026rsquo;s Coordinating Centre. Brain [Internet]. 2013 [cited 2024 Jul 19];136:2697\u0026ndash;706. Available from: https://dx.doi.org/10.1093/brain/awt188\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eXu F, Grande AM, Robinson JK, Previti ML, Vasek M, Davis J, et al. \u003c/span\u003eEarly-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid \u0026beta;-protein precursor transgenic mice. Neuroscience. 2007;146:98\u0026ndash;107.\u003c/li\u003e\n\u003cli\u003eWang L, Pavlou S, Du X, Bhuckory M, Xu H, Chen M. Glucose transporter 1 critically controls microglial activation through facilitating glycolysis. Mol Neurodegener [Internet]. 2019 [cited 2025 May 12];14. Available from: https://doi.org/10.1186/s13024-019-0305-9\u003c/li\u003e\n\u003cli\u003eOh S hee, Choi Y bok, Kim J hyun, Weihl CC, Ju J sun. Comparisons of ELISA and Western blot assays for detection of autophagy flux. Data Brief [Internet]. 2017 [cited 2024 Jul 19];13:696. Available from: /pmc/articles/PMC5506881/\u003c/li\u003e\n\u003cli\u003eJensen K, Krusenstjerna-Hafstr\u0026oslash;m R, Lohse J, Petersen KH, Derand H. A novel quantitative immunohistochemistry method for precise protein measurements directly in formalin-fixed, paraffin-embedded specimens: analytical performance measuring HER2. Modern Pathology [Internet]. 2017 [cited 2024 Jul 26];30:180\u0026ndash;93. Available from: http://www.modernpathology.org/article/S089339522201273X/fulltext\u003c/li\u003e\n\u003cli\u003eGil-Iturbe E, Solas M, Cuadrado-Tejedo M, Ram\u0026iacute;rez MJ, Lostao MP. Expression of the glucose transporter GLUT12 in mouse models of Alzheimer\u0026rsquo;s disease and aging. Acta Physiologica [Internet]. 2019;227:83\u0026ndash;4. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L631555151\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eJankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. \u003c/span\u003eMutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet [Internet]. 2004 [cited 2024 Jun 25];13:159\u0026ndash;70. Available from: https://pubmed.ncbi.nlm.nih.gov/14645205/\u003c/li\u003e\n\u003cli\u003eVolianskis A, K\u0026oslash;stner R, M\u0026oslash;lgaard M, Hass S, Jensen MS. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1\u0026delta;E9-deleted transgenic mice model of \u0026szlig;-amyloidosis. Neurobiol Aging [Internet]. 2010 [cited 2024 Jun 25];31:1173\u0026ndash;87. Available from: https://pubmed.ncbi.nlm.nih.gov/18790549/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eKamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AHP, et al. \u003c/span\u003eGFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One [Internet]. 2012 [cited 2024 Jun 25];7. Available from: https://pubmed.ncbi.nlm.nih.gov/22912745/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eMa H-H, Wan C, Zhang L-D, Zhang R-R, Peng D, Qiao L-J, et al. \u003c/span\u003eSodium tanshinone IIA sulfonate improves cognitive impairment via regulating A\u0026beta; transportation in AD transgenic mouse model. Metab Brain Dis [Internet]. 2022 [cited 2024 May 21];37:989\u0026ndash;1001. Available from: https://link.springer.com/10.1007/s11011-022-00911-y\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eHooijmans CR, Graven C, Dederen PJ, Tanila H, van Groen T, Kiliaan AJ. \u003c/span\u003eAmyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice. Brain Res [Internet]. 2007;1181:93\u0026ndash;103. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L350050914\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eChen F, He Y, Wang P, Wei P, Feng H, Rao Y, et al. Banxia Xiexin decoction ameliorated cognition via the regulation of insulin pathways and glucose transporters in the hippocampus of APPswe/PS1dE9 mice. Int J Immunopathol Pharmacol [Internet]. 2018 [cited 2024 May 21];32:205873841878006. Available from: http://journals.sagepub.com/doi/10.1177/2058738418780066\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eGuo Y, Ma X, Li P, Dong S, Huang X, Ren X, et al. \u003c/span\u003eHigh-fat diet induced discrepant peripheral and central nervous systems insulin resistance in APPswe/PS1dE9 and wild-type C57BL/6J mice. Aging [Internet]. 2020;13:1236\u0026ndash;50. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L633663817\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eZerbi V, Jansen D, Dederen PJ, Veltien A, Hamans B, Liu Y, et al. \u003c/span\u003eMicrovascular cerebral blood volume changes in aging APPswe/PS1dE9 AD mouse model: a voxel-wise approach. Brain Struct Funct [Internet]. 2013 [cited 2024 May 21];218:1085\u0026ndash;98. Available from: http://link.springer.com/10.1007/s00429-012-0448-8\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eZhang S, Zhu L, Peng Y, Zhang L, Chao F, Jiang L, et al. \u003c/span\u003eLong-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice. J Neuroinflammation [Internet]. 2022 [cited 2024 May 21];19:34. Available from: https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-022-02401-5\u003c/li\u003e\n\u003cli\u003eKhandelwal M, Manglani K, Upadhyay P, Azad M, Gupta S. AdipoRon induces AMPK activation and ameliorates Alzheimer\u0026rsquo;s like pathologies and associated cognitive impairment in APP/PS1 mice. Neurobiol Dis [Internet]. 2022 [cited 2024 May 21];174:105876. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0969996122002686\u003c/li\u003e\n\u003cli\u003eMechlovich D, Amit T, Bar-Am O, Mandel S, Youdim MBH, Weinreb O. The novel multi-target iron chelator, M30 modulates HIF-1\u0026alpha;-related glycolytic genes and insulin signaling pathway in the frontal cortex of APP/PS1 Alzheimer\u0026rsquo;s disease mice. Curr Alzheimer Res [Internet]. 2014;11:119\u0026ndash;27. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L372738595\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eRadde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. \u003c/span\u003eAbeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep [Internet]. 2006 [cited 2024 Jun 25];7:940\u0026ndash;6. Available from: https://pubmed.ncbi.nlm.nih.gov/16906128/\u003c/li\u003e\n\u003cli\u003eRupp NJ, Wegenast-Braun BM, Radde R, Calhoun ME, Jucker M. Early onset amyloid lesions lead to severe neuritic abnormalities and local, but not global neuron loss in APPPS1 transgenic mice. Neurobiol Aging [Internet]. 2011 [cited 2024 Jun 25];32:2324.e1-2324.e6. Available from: https://pubmed.ncbi.nlm.nih.gov/20970889/\u003c/li\u003e\n\u003cli\u003eSerneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horr\u0026eacute; K, Van Houtvin T, et al. gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer\u0026rsquo;s disease. Science [Internet]. 2009 [cited 2024 Jun 25];324:639\u0026ndash;42. Available from: https://pubmed.ncbi.nlm.nih.gov/19299585/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003ePang R, Wang X, Pei F, Zhang W, Shen J, Gao X, et al. \u003c/span\u003eRegular Exercise Enhances Cognitive Function and Intracephalic GLUT Expression in Alzheimer\u0026rsquo;s Disease Model Mice. Journal of Alzheimer\u0026rsquo;s Disease [Internet]. 2019 [cited 2024 May 21];72:83\u0026ndash;96. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress\u0026amp;doi=10.3233/JAD-190328\u003c/li\u003e\n\u003cli\u003eQin G, Dong Y, Liu Z, Gong Z, Gao C, Zheng M, et al. Shen-Zhi-Ling oral liquid ameliorates cerebral glucose metabolism disorder in early AD via insulin signal transduction pathway in vivo and in vitro. Chinese Medicine (United Kingdom) [Internet]. 2021;16. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2014344048\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eWu H, Wu Z, Shi W, Gao H, Wu H, Bian F, et al. Effects of progesterone on glucose uptake in neurons of Alzheimer\u0026rsquo;s disease animals and cell models. Life Sci [Internet]. 2019 [cited 2024 May 21];238:116979. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0024320519309063\u003c/li\u003e\n\u003cli\u003eWang Y, Ruan Y, Cui C, Wang X. Jiaotaiwan improves brain glucose metabolism in a mouse model of Alzheimer\u0026rsquo;s disease by activating the PI3K/AKT signaling pathway. Nan Fang Yi Ke Da Xue Xue Bao [Internet]. 2024;44:894\u0026ndash;903. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L644504418\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eQi G, Tang H, Gong P, Liu Y, He C, Hu J, et al. Sex-specific hypothalamic neuropathology and glucose metabolism in an amyloidosis transgenic mouse model of Alzheimer\u0026rsquo;s disease. Cell Biosci. 2024;14.\u003c/li\u003e\n\u003cli\u003eOakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u0026rsquo;s disease mutations: potential factors in amyloid plaque formation. J Neurosci [Internet]. 2006 [cited 2024 Jun 25];26:10129\u0026ndash;40. Available from: https://pubmed.ncbi.nlm.nih.gov/17021169/\u003c/li\u003e\n\u003cli\u003ePuris E, Saveleva L, Auriola S, Gynther M, Kanninen KM, Fricker G. Sex-specific changes in protein expression of membrane transporters in the brain cortex of 5xFAD mouse model of Alzheimer\u0026rsquo;s disease. Front Pharmacol [Internet]. 2024;15. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2029281634\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eKim J, Kang S, Chang K-A. Effect of cx-DHED on Abnormal Glucose Transporter Expression Induced by AD Pathologies in the 5xFAD Mouse Model. Int J Mol Sci [Internet]. 2022 [cited 2024 May 21];23:10602. Available from: https://www.mdpi.com/1422-0067/23/18/10602\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eNyirenda JT, Henrion MYR, Nyasulu V, Msakwiza M, Nedi W, Thole H, et al. \u003c/span\u003eExamination of ELISA against PCR for assessing treatment efficacy against Cryptosporidium in a clinical trial context. PLoS One [Internet]. 2023 [cited 2024 Jul 26];18. Available from: /pmc/articles/PMC10490871/\u003c/li\u003e\n\u003cli\u003eOddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer\u0026rsquo;s Disease with plaques and tangles: Intracellular A\u0026beta; and synaptic dysfunction. Neuron [Internet]. 2003 [cited 2024 Jun 25];39:409\u0026ndash;21. Available from: https://pubmed.ncbi.nlm.nih.gov/12895417/\u003c/li\u003e\n\u003cli\u003eCaruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike CJ, et al. Age-related changes in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging [Internet]. 2013 [cited 2024 Jun 25];34:1080. Available from: /pmc/articles/PMC3545103/\u003c/li\u003e\n\u003cli\u003eBillings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer\u0026rsquo;s disease-related cognitive deficits in transgenic mice. Neuron [Internet]. 2005 [cited 2024 Jun 25];45:675\u0026ndash;88. Available from: https://pubmed.ncbi.nlm.nih.gov/15748844/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eYan D, Qu X, Chen M, Wang J, Li X, Zhang Z, et al. \u003c/span\u003eFunctionalized curcumin/ginsenoside Rb1 dual-loaded liposomes: Targeting the blood-brain barrier and improving pathological features associated in APP/PS-1 mice. J Drug Deliv Sci Technol [Internet]. 2023;86. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2025130168\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eLi Z, Zhang Y, Meng X, Li M, Cao W, Yang J, et al. \u003c/span\u003eA novel DPP-4 inhibitor Gramcyclin A attenuates cognitive deficits in APP/PS1/tau triple transgenic mice via enhancing brain GLP-1-dependent glucose uptake. Phytotherapy Research [Internet]. 2022;36:1297\u0026ndash;309. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2014864426\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eDo TM, Alata W, Dodacki A, Traversy M-T, Chacun H, Pradier L, et al. Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer\u0026rsquo;s disease. Neuropharmacology [Internet]. 2014;81:311\u0026ndash;7. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L372677562\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eYan F, Liu J, Chen M-X, Zhang Y, Wei S-J, Jin H, et al. Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3\u0026times;Tg-AD mice. Neural Regen Res [Internet]. 2023;18:183\u0026ndash;8. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L639663625\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eHwang DY, Chae KR, Kang TS, Hwang JH, Lim CH, Kang HK, et al. \u003c/span\u003eAlterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer\u0026rsquo;s disease. FASEB J [Internet]. 2002 [cited 2024 Jun 25];16:805\u0026ndash;13. Available from: https://pubmed.ncbi.nlm.nih.gov/12039862/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eLee YJ, Kim JE, Hwang IS, Kwak MH, Lee JH, Jung YJ, et al. \u003c/span\u003eAlzheimer\u0026rsquo;s phenotypes induced by overexpression of human presenilin 2 mutant proteins stimulate significant changes in key factors of glucose metabolism. Mol Med Rep [Internet]. 2013;7:1571\u0026ndash;8. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L368691964\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eHampton DW, Webber DJ, Bilican B, Goedert M, Spillantini MG, Chandran S. Cell-Mediated Neuroprotection in a Mouse Model of Human Tauopathy. The Journal of Neuroscience [Internet]. 2010 [cited 2024 Jun 25];30:9973. Available from: /pmc/articles/PMC6633376/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eXu H, R\u0026ouml;sler TW, Carlsson T, de Andrade A, Bruch J, H\u0026ouml;llerhage M, et al. \u003c/span\u003eMemory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice. Neuropathol Appl Neurobiol [Internet]. 2014 [cited 2024 Jun 25];40:833\u0026ndash;43. Available from: https://pubmed.ncbi.nlm.nih.gov/24865638/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eMcGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, et al. \u003c/span\u003eAbeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron [Internet]. 2005 [cited 2024 Jun 25];47:191\u0026ndash;9. Available from: https://pubmed.ncbi.nlm.nih.gov/16039562/\u003c/li\u003e\n\u003cli\u003eDey M, Singh RK. Neurotoxic effects of aluminium exposure as a potential risk factor for Alzheimer\u0026rsquo;s disease. Pharmacol Rep [Internet]. 2022 [cited 2024 Jun 19];74:439\u0026ndash;50. Available from: https://pubmed.ncbi.nlm.nih.gov/35088386/\u003c/li\u003e\n\u003cli\u003eYang L, Wang Y, Li Z, Wu X, Mei J, Zheng G. Brain targeted peptide-functionalized chitosan nanoparticles for resveratrol delivery: Impact on insulin resistance and gut microbiota in obesity-related Alzheimer\u0026rsquo;s disease. Carbohydr Polym [Internet]. 2023 [cited 2024 May 21];310:120714. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0144861723001789\u003c/li\u003e\n\u003cli\u003eAbu-Taweel GM, Al-Mutary MG. Pomegranate juice reverses AlCl3-Induced neurotoxicity and improves learning and memory in female mice. Environ Res [Internet]. 2021;199:111270. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0013935121005648\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eKumar R, Kumar R, Sharma N, Khurana N, Singh SK, Satija S, et al. \u003c/span\u003ePharmacological evaluation of bromelain in mouse model of Alzheimer\u0026rsquo;s disease. Neurotoxicology [Internet]. 2022 [cited 2024 Jul 1];90:19\u0026ndash;34. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0161813X22000286\u003c/li\u003e\n\u003cli\u003eCuciniello R, Luongo D, Ferramosca A, Lunetti P, Rotondi-Aufiero V, Crispi S, et al. Conjugated linoleic acid downregulates Alzheimer\u0026rsquo;s hallmarks in aluminum mouse model through an Nrf2-mediated adaptive response and increases brain glucose transporter levels. Free Radic Biol Med [Internet]. 2022 [cited 2024 May 21];191:48\u0026ndash;58. Available from: https://linkinghub.elsevier.com/retrieve/pii/S089158492200555X\u003c/li\u003e\n\u003cli\u003eMayer G, Nitsch R, Hoyer S. Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res. 1990;532:95\u0026ndash;100.\u003c/li\u003e\n\u003cli\u003eKnezovic A, Osmanovic-Barilar J, Curlin M, Hof PR, Simic G, Riederer P, et al. Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer\u0026rsquo;s disease. J Neural Transm [Internet]. 2015 [cited 2024 Jun 26];122:577\u0026ndash;92. Available from: https://link.springer.com/article/10.1007/s00702-015-1394-4\u003c/li\u003e\n\u003cli\u003eSalkovic-Petrisic M, Tribl F, Schmidt M, Hoyer S, Riederer P. Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem [Internet]. 2006;96:1005\u0026ndash;15. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L43433021\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eSalkovic-Petrisic M, Osmanovic-Barilar J, Br\u0026uuml;ckner MK, Hoyer S, Arendt T, Riederer P. Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer\u0026rsquo;s disease: A long-term follow up study. J Neural Transm [Internet]. 2011 [cited 2024 Jun 26];118:765\u0026ndash;72. Available from: https://link.springer.com/article/10.1007/s00702-011-0651-4\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eDeng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong C-X. \u003c/span\u003eDysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: Implication for Alzheimer\u0026rsquo;s disease. American Journal of Pathology [Internet]. 2009;175:2089\u0026ndash;98. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L358071935\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eOsmanovic Barilar J, Knezovic A, Gr\u0026uuml;nblatt E, Riederer P, Salkovic-Petrisic M. Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer\u0026rsquo;s disease. J Neural Transm [Internet]. 2015 [cited 2024 Jun 26];122:565\u0026ndash;76. Available from: https://link.springer.com/article/10.1007/s00702-014-1323-y\u003c/li\u003e\n\u003cli\u003ePrickaerts J, Fahrig T, Blokland A. Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis. Behavioural Brain Research. 1999;102:73\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eKraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, et al. In Vivo Cross-sectional Characterization of Cerebral Alterations Induced by Intracerebroventricular Administration of Streptozotocin. PLoS One [Internet]. 2012 [cited 2024 Jun 26];7:e46196. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046196\u003c/li\u003e\n\u003cli\u003eBiasibetti R, Almeida dos Santos JP, Rodrigues L, Wartchow KM, Suardi LZ, Nardin P, et al. Hippocampal changes in STZ-model of Alzheimer\u0026rsquo;s disease are dependent on sex. Behavioural Brain Research. 2017;316:205\u0026ndash;14.\u003c/li\u003e\n\u003cli\u003eBiswas J, Gupta S, Verma DK, Gupta P, Singh A, Tiwari S, et al. Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer\u0026rsquo;s like pathology. Cell Signal [Internet]. 2018;42:211\u0026ndash;26. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L619123497\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003ePilipenko V, Narbute K, Pupure J, Langrate IK, Muceniece R, Klu\u0026scaron;a V. Neuroprotective potential of antihyperglycemic drug metformin in streptozocin-induced rat model of sporadic Alzheimer\u0026rsquo;s disease. Eur J Pharmacol [Internet]. 2020 [cited 2024 May 21];881:173290. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014299920303824\u003c/li\u003e\n\u003cli\u003eSalkovic-Petrisic M, Knezovic A, Osmanovic-Barilar J, Reutter W. Therapeutic effect of oral galactose treatment in a rat model of sporadic Alzheimer\u0026rsquo;s disease. Alzheimer\u0026rsquo;s and Dementia [Internet]. 2014;10:P464. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L71627944\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eSamman WA, Selim SM, El Fayoumi HM, El-Sayed NM, Mehanna ET, Hazem RM. Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer\u0026rsquo;s Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism. Pharmaceuticals [Internet]. 2023;16. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2023427699\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eBazzari FH, Abdallah DM, El-Abhar HS. Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer\u0026rsquo;s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats. Molecules [Internet]. 2019;24. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L628137151\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eRadfar F, Shahbazi M, Tahmasebi Boroujeni S, Arab Ameri E, Farahmandfar M. Moderate aerobic training enhances the effectiveness of insulin therapy through hypothalamic IGF1 signaling in rat model of Alzheimer\u0026rsquo;s disease. Sci Rep [Internet]. 2024 [cited 2025 Jul 1];14:15996. Available from: https://www.nature.com/articles/s41598-024-66637-2\u003c/li\u003e\n\u003cli\u003ePuris E, Auriola S, Petralla S, Hartman R, Gynther M, de Lange ECM, et al. Altered protein expression of membrane transporters in isolated cerebral microvessels and brain cortex of a rat Alzheimer\u0026rsquo;s disease model. Neurobiol Dis. 2022;169:105741.\u003c/li\u003e\n\u003cli\u003eMa Y, Sun W, Bai J, Gao F, Ma H, Liu H, et al. Targeting blood brain barrier\u0026mdash;Remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats. CNS Neurosci Ther [Internet]. 2024;30. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2028621920\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eCohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric a\u0026beta;, and frank neuronal loss. J Neurosci [Internet]. 2013 [cited 2024 Jun 26];33:6245\u0026ndash;56. Available from: https://pubmed.ncbi.nlm.nih.gov/23575824/\u003c/li\u003e\n\u003cli\u003eKlakotskaia D, Agca C, Richardson RA, Stopa EG, Schachtman TR, Agca Y. Memory deficiency, cerebral amyloid angiopathy, and amyloid-\u0026beta; plaques in APP+PS1 double transgenic rat model of Alzheimer\u0026rsquo;s disease. PLoS One [Internet]. 2018 [cited 2024 Jun 26];13. Available from: https://pubmed.ncbi.nlm.nih.gov/29641600/\u003c/li\u003e\n\u003cli\u003eAgca C, Klakotskaia D, Schachtman TR, Chan AW, Lah JJ, Agca Y. Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention. BMC Neurosci [Internet]. 2016 [cited 2024 Jun 26];17. Available from: https://pubmed.ncbi.nlm.nih.gov/27388605/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eKanekiyo T, Cirrito JR, Liu CC, Shinohara M, Li J, Schuler DR, et al. \u003c/span\u003eNeuronal clearance of amyloid-\u0026beta; by endocytic receptor LRP1. J Neurosci [Internet]. 2013 [cited 2024 Jul 26];33:19276\u0026ndash;83. Available from: https://pubmed.ncbi.nlm.nih.gov/24305823/\u003c/li\u003e\n\u003cli\u003eZhang Y-H, Yan X-Z, Xu S-F, Pang Z-Q, Li L-B, Yang Y, et al. \u0026alpha;-Lipoic Acid Maintains Brain Glucose Metabolism via BDNF/TrkB/HIF-1\u0026alpha; Signaling Pathway in P301S Mice. Front Aging Neurosci [Internet]. 2020;12. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L632736565\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eKnezovic A, Loncar A, Homolak J, Smailovic U, Osmanovic Barilar J, Ganoci L, et al. Rat brain glucose transporter-2, insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer\u0026rsquo;s disease? J Neural Transm [Internet]. 2017;124:695\u0026ndash;708. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L615890534\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eSalkovic-Petrisic M, Osmanovic-Barilar J, Knezovic A, Hoyer S, Mosetter K, Reutter W. Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin. Neuropharmacology [Internet]. 2014;77:68\u0026ndash;80. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L370075184\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eSajadi E, Sajedianfard J, Hosseinzadeh S, Taherianfard M. Effect of insulin and cinnamon extract on spatial memory and gene expression of GLUT1, 3, and 4 in streptozotocin-induced Alzheimer\u0026rsquo;s model in rats. Iran J Basic Med Sci [Internet]. 2023;26:680\u0026ndash;7. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L2025285910\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eGong CX, Liu F, Grundke-Iqbal I, Iqbal K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis [Internet]. 2006 [cited 2024 Jul 25];9:1\u0026ndash;12. Available from: https://pubmed.ncbi.nlm.nih.gov/16627930/\u003c/li\u003e\n\u003cli\u003eLiu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer\u0026rsquo;s disease. Proc Natl Acad Sci U S A [Internet]. 2004 [cited 2024 Jul 25];101:10804. Available from: /pmc/articles/PMC490015/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eVitek MP, Araujo JA, Fosse M, Greenberg BD, Howell GR, Rizzo SJS, et al. \u003c/span\u003eTranslational animal models for Alzheimer\u0026rsquo;s disease: An Alzheimer\u0026rsquo;s Association Business Consortium Think Tank. Alzheimer\u0026rsquo;s \u0026amp; Dementia : Translational Research \u0026amp; Clinical Interventions [Internet]. 2020 [cited 2024 Jul 26];6. Available from: /pmc/articles/PMC7798310/\u003c/li\u003e\n\u003cli\u003eCummings JL, Morstorf T, Zhong K. Alzheimer\u0026rsquo;s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther [Internet]. 2014 [cited 2024 Jul 26];6:37. Available from: /pmc/articles/PMC4095696/\u003c/li\u003e\n\u003cli\u003eGr\u0026uuml;nblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S. Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem [Internet]. 2007;101:757\u0026ndash;70. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L46633313\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eSalkovic-Petrisic M, Osmanovic J, Gr\u0026uuml;nblatt E, Riederer P, Hoyer S. Modeling Sporadic Alzheimer\u0026rsquo;s Disease: The Insulin Resistant Brain State Generates Multiple Long-Term Morphobiological Abnormalities Including Hyperphosphorylated Tau Protein and Amyloid-\u0026beta;. Journal of Alzheimer\u0026rsquo;s Disease [Internet]. 2009;18:729\u0026ndash;50. Available from: https://www.medra.org/servlet/aliasResolver?alias=iospress\u0026amp;doi=10.3233/JAD-2009-1184\u003c/li\u003e\n\u003cli\u003ePedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol [Internet]. 2006 [cited 2024 Jul 26];199:265\u0026ndash;73. Available from: https://pubmed.ncbi.nlm.nih.gov/16515786/\u003c/li\u003e\n\u003cli\u003eReger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging [Internet]. 2006 [cited 2024 Jul 26];27:451\u0026ndash;8. Available from: https://pubmed.ncbi.nlm.nih.gov/15964100/\u003c/li\u003e\n\u003cli\u003eReger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis [Internet]. 2008 [cited 2024 Jul 26];13:323\u0026ndash;31. Available from: https://pubmed.ncbi.nlm.nih.gov/18430999/\u003c/li\u003e\n\u003cli\u003eWatson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry [Internet]. 2005 [cited 2024 Jul 26];13:950\u0026ndash;8. Available from: https://pubmed.ncbi.nlm.nih.gov/16286438/\u003c/li\u003e\n\u003cli\u003eSalkovic-Petrisic M, Hoyer S. Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl [Internet]. 2007 [cited 2024 Jul 26];217\u0026ndash;33. Available from: https://pubmed.ncbi.nlm.nih.gov/17982898/\u003c/li\u003e\n\u003cli\u003eCorreia SC, Santos RX, Perry G, Zhu X, IMoreira PI, Smith MA. Insulin-Resistant Brain State: the culprit in sporadic Alzheimer\u0026rsquo;s Disease? Ageing Res Rev [Internet]. 2011 [cited 2024 Jul 26];10:264. Available from: /pmc/articles/PMC3056939/\u003c/li\u003e\n\u003cli\u003eBenomar Y, Naour N, Aubourg A, Bailleux V, Gertler A, Djiane J, et al. Insulin and Leptin Induce Glut4 Plasma Membrane Translocation and Glucose Uptake in a Human Neuronal Cell Line by a Phosphatidylinositol 3-Kinase- Dependent Mechanism. Endocrinology [Internet]. 2006 [cited 2024 Jul 25];147:2550\u0026ndash;6. Available from: https://dx.doi.org/10.1210/en.2005-1464\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eZhao L, Teter B, Morihara T, Lim GP, Ambegaokar SS, Ubeda OJ, et al. \u003c/span\u003eInsulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer\u0026rsquo;s disease intervention. J Neurosci [Internet]. 2004 [cited 2024 Jul 25];24:11120\u0026ndash;6. Available from: https://pubmed.ncbi.nlm.nih.gov/15590928/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eErtekin-Taner N, Allen M, Fadale D, Scanlin L, Younkin L, Petersen RC, et al. \u003c/span\u003eGenetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat [Internet]. 2004 [cited 2024 Jul 25];23:334\u0026ndash;42. Available from: https://pubmed.ncbi.nlm.nih.gov/15024728/\u003c/li\u003e\n\u003cli\u003eZelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J [Internet]. 1998 [cited 2024 Jul 25];17:5085\u0026ndash;94. Available from: https://pubmed.ncbi.nlm.nih.gov/9724644/\u003c/li\u003e\n\u003cli\u003eChen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem [Internet]. 2001 [cited 2024 Jul 25];276:9519\u0026ndash;25. Available from: https://pubmed.ncbi.nlm.nih.gov/11120745/\u003c/li\u003e\n\u003cli\u003eMullins RJ, Diehl TC, Chia CW, Kapogiannis D. Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer\u0026rsquo;s Disease. Front Aging Neurosci [Internet]. 2017 [cited 2024 May 21];9. Available from: http://journal.frontiersin.org/article/10.3389/fnagi.2017.00118/full\u003c/li\u003e\n\u003cli\u003ePernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol [Internet]. 2014 [cited 2024 Jul 26];10:143\u0026ndash;56. Available from: https://pubmed.ncbi.nlm.nih.gov/24393785/\u003c/li\u003e\n\u003cli\u003eDing F, Yao J, Rettberg JR, Chen S, Brinton RD. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer\u0026rsquo;s mouse brain: Implication for bioenergetic intervention. PLoS One [Internet]. 2013;8. Available from: https://www.embase.com/search/results?subaction=viewrecord\u0026amp;id=L372232393\u0026amp;from=export\u003c/li\u003e\n\u003cli\u003eAbdul Muneer PM, Alikunju S, Szlachetka AM, Murrin LC, Haorah J. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction. Mol Neurodegener [Internet]. 2011 [cited 2024 Jul 26];6:23. Available from: /pmc/articles/PMC3073895/\u003c/li\u003e\n\u003cli\u003eAngeloni C, Barbalace MC, Hrelia S. Icariin and Its Metabolites as Potential Protective Phytochemicals Against Alzheimer\u0026rsquo;s Disease. Front Pharmacol [Internet]. 2019 [cited 2024 Jul 26];10. Available from: /pmc/articles/PMC6433697/\u003c/li\u003e\n\u003cli\u003e\u003cspan lang=\"DA\"\u003eLi X, Wang Y, Shi P, Liu Y, Li T, Liu S, et al. \u003c/span\u003eIcariin treatment reduces blood glucose levels in type 2 diabetic rats and protects pancreatic function. Exp Ther Med [Internet]. 2020 [cited 2024 Jul 26];19. Available from: https://pubmed.ncbi.nlm.nih.gov/32256750/\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease, glucose transporters, brain metabolism, Alzheimer's disease models","lastPublishedDoi":"10.21203/rs.3.rs-7374065/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7374065/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe brain requires a constant glucose supply to fuel energy production for numerous cellular functions. Glucose is transported into the brain by means of specialized glucose transporter proteins (GLUTs), which ensure transport across the blood-brain barrier (BBB) and uptake in neurons and glia. Dysregulation of brain glucose metabolism has been implicated in contributing to neurodegenerative diseases, including Alzheimer's Disease (AD). While development of neuronal amyloid-beta plaques and tau-containing tangles both occur in AD, recent research suggests that metabolic changes, including GLUT alterations, could play a crucial role in disease progression. This review investigates alterations in GLUT expression occurring in AD patients and related rodent models of AD. Reduction of GLUT1 and GLUT3, key transporters for glucose transport across the BBB and cellular uptake in the brain, was consistently observed in AD patients. These alterations were associated with AD pathology and cognitive decline in several studies. While most rodent studies replicate the findings in human AD, others discern diverse results, highlighting the complexity of AD modeling in laboratory animals. This was further supported by our own original data showing divergent GLUT1 mRNA and protein alterations in Tg-SwDI and 5xFAD mice. GLUT2 and GLUT4 have been less studied, but studies in AD patients suggest an increase in GLUT2 expression, whereas a possible correlation between AD and GLUT4 is absent. Results from studies of GLUT2 and GLUT4 expression in rodent models of AD were too inconsistent to make any clear conclusions. Contributing to the complexity of GLUT's role in AD pathophysiology, rodent studies suggest that GLUT1 deficiency not only contributes to but also exacerbates AD progression by further restricting glucose transport to the brain, leading to intensified metabolic impairments. Together, these findings support that restoring the expression of GLUTs denotes a potential therapeutic target for limiting disease progression in AD. However, due to the divergent results across various studies, it is challenging to draw definitive conclusions regarding GLUT expression in rodent AD models. Some models may not fully replicate the GLUT and metabolic changes observed in AD, posing a limitation that is crucial to consider in future studies to enhance their translational potential.\u003c/p\u003e","manuscriptTitle":"Systematic Review of glucose transporter alterations in human Alzheimer’s disease and rodent Alzheimer’s disease models","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-20 08:09:52","doi":"10.21203/rs.3.rs-7374065/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fc6777cb-83f5-49aa-9f5a-43b984071562","owner":[],"postedDate":"August 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-07T23:08:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-20 08:09:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7374065","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7374065","identity":"rs-7374065","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}