APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption

APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption | 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 Research Article APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption Marco Matos, Aymeric Oliveira, Isabelle Matias, Anna Le Boulch, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7320776/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Feb, 2026 Read the published version in Alzheimer's Research & Therapy → Version 1 posted 14 You are reading this latest preprint version Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder thought to result from complex interactions between genetic and environmental risk factors. The APOE-ε4 allele is the strongest genetic contributor to late-onset AD, while a Western diet - high in saturated fats and refined sugars - is a major lifestyle-related risk factor associated with AD progression. However, how these two factors interact at an early stage of the disease remains unclear. In this study, we examined their combined impact on hippocampal synaptic transmission and plasticity in an AD mouse model and evaluated whether supplementation with d-serine, the key NMDAR co-agonist, could reverse the resulting deficits. Methods To assess the combined effects of genetic and dietary risk factors on synaptic function, we crossed APP/PS1 mice with APOE-ε4 KI mice andgenerated four mouse lines: wild-type, APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Hippocampal synaptic transmission and plasticity, NMDAR function and d- and l-serine levels were evaluated using a combination of electrophysiological recordings, pharmacological interventions and capillary electrophoresis in brain slices, under either control or Western diet conditions. Results A significant impairment of both basal excitatory synaptic transmission and long-term potentiation (LTP) was detected in APP/PS1 mice by 9 months of age. These deficits were significantly more pronounced in APP/PS1/APOE-ε4 mice. Notably, Western diet accelerated these impairments, with significant deficits already present at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice. Mechanistically, these impairments were associated with reduced d-serine availability and NMDAR hypofunction at CA3-CA1 synapses. Conclusions This study provides the first direct evidence of a specific and synergistic interaction between the APOE-ε4 genotype and Western diet in advancing and exacerbating hippocampal synaptic dysfunction in an AD mouse model. These findings highlight d-serine/NMDAR signaling as a key mechanistic pathway through which genetic and environmental risk factors converge in early AD, and underscore the potential of targeting astrocytic d-serine biosynthetic pathways as a promising therapeutic strategy for APOE-ε4 carriers at risk for late-onset AD. Trial registration Not applicable Alzheimer’s disease APOE-ε4 Western diet NMDAR d-serine hippocampus synaptic plasticity APP/PS1 mice gene-environment interaction. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background Alzheimer’s disease (AD) is the most common chronic neurodegenerative disorder, clinically characterized by a progressive decline of cognitive functions such as learning and memory, ultimately leading to severe dementia and functional decline. It is estimated that over 50 million people worldwide are affected by AD, with projections suggesting this number will double by 2040 (source: www.alz.co.uk ). Although the exact etiology remains debated, hallmark pathological features include impaired glucose metabolism, followed by accumulation of extracellular amyloid-beta (Aβ) plaques, intracellular neurofibrillary tangles, and inflammation - ultimately culminating in neuronal impairment and death ( 1 , 2 ). Synaptic dysfunction, particularly in the limbic cortex, is believed to play a central role in disease progression. Memory impairments in AD are closely associated with reduced synaptic density and efficacy, especially in the hippocampus, where glutamatergic synapses are highly vulnerable ( 3 – 5 ). Several studies have reported early synaptic deficits in AD, notably at hippocampal glutamatergic synapses, including reduced dendritic spine density and impaired long-term potentiation (LTP), a key form of synaptic plasticity critical for learning and memory and among the earliest functions disrupted in AD ( 6 , 7 ). LTP at CA3-CA1 synapses is primarily mediated by postsynaptic NMDA receptor activation, which initiates intracellular signaling cascades that enhance synaptic strength and connectivity ( 8 , 9 ). Its early disruption in AD underscores the vulnerability of these synapses and highlights LTP impairment as a key pathological hallmark. We have previously shown that deficits in synaptic plasticity and memory in the triple-transgenic mouse model (3xTg-AD) are linked to reduced astrocytic glycolysis and therefore reduced biosynthesis of l -serine and d -serine ( 10 , 11 ). As an essential co-agonist of synaptic NMDA receptors (NMDARs) at hippocampal CA3-CA1 synapses ( 12 – 14 ), d -serine plays a key role in NMDAR-dependent synaptic plasticity. Accordingly, reduced d -serine availability has been consistently associated with impaired NMDAR function and cognitive decline in both AD models ( 15 , 16 ) and during normal aging ( 17 ). While most transgenic models of AD reflect familial (early-onset) forms, which account for only 5–10% of cases ( 18 ), the majority of AD cases are sporadic and late-onset. The strongest genetic risk factor for late-onset AD is the presence of the apolipoprotein E ɛ4 allele (APOE-ɛ4) ( 19 , 20 ), which increases the risk of AD by 3- to 15-fold ( 21 – 23 ). Though the exact mechanisms by which APOE-ɛ4 promotes AD are still under investigation, evidence suggests it contributes to increased Aβ deposition, cerebrovascular dysfunction, and altered cerebral metabolism ( 24 , 25 ). In APOE-ε4 knock-in mice, impairments in synaptic plasticity, reductions in dendritic spine density, and increased neuronal hyperexcitability have been observed, further implicating APOE-ε4 in AD-related synaptic vulnerability ( 26 – 28 ). Beyond genetic predisposition, environmental factors such as diet significantly influence late-onset AD risk. Both clinical and preclinical evidence strongly associate Western dietary patterns - characterized by high levels of saturated fats, refined sugars, and low nutrient content - with cognitive decline and increased AD susceptibility (reviewed in ( 29 , 30 ). Notably, Western diet-induced pathologies such as neuroinflammation, glial activation, and Aβ accumulation overlap mechanistically with those linked to APOE-ɛ4 ( 31 , 32 ). However, the specific interactions between APOE-ɛ4 and Western diet in modulating synaptic transmission and plasticity in AD remain poorly understood. We hypothesized that the combination of genetic risk (APOE-ɛ4, APP, PS1) and acquired risk (Western diet, aging) factors would exacerbate synaptic pathology in an AD mouse model. To test this, we investigated hippocampal synaptic transmission and plasticity in APP/PS1 mice, with and without the APOE-ɛ4 allele, under control diet or Western diet conditions. Our findings demonstrate for the first time that the APOE-ɛ4 genotype amplifies, and a Western diet intake accelerates, hippocampal synaptic deficits in APP/PS1 mice through a synergistic interaction. Remarkably, these impairments were rescued by exogenous d -serine supplementation, implicating disrupted d -serine biosynthesis and impaired NMDAR-dependent plasticity as key mechanisms underlying this gene-environment interaction. Methods Animals APPswe/PS1dE9 (APP/PS1) mice, a widely used model of Alzheimer’s disease (AD) ( 25 ), were obtained from The Jackson Laboratory (strain number 034832-JAX). APOE-ε4 KI, a mouse line pertinent to AD and atherosclerosis, with human APOE-ε4 sequences replacing those on the mouse APOE gene ( 24 ), was also obtained from The Jackson Laboratory (strain number 027894-JAX). These two lines were crossed to generate four genotypes: wild-type (wt), APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Mice of either sex were used in all experiments. All procedures were conducted in strict accordance with the European Union directive 2010/63/EU for animal care and use, and were approved by the French Ministry of Agriculture and Fisheries and the local ethical committee. Every effort was made to minimize animal suffering. Animal care was overseen by veterinarians and trained technicians specialized in rodent husbandry. Animals were housed under standard environmental conditions (12-h light-dark cycle, temperature: 22 ± 1°C and humidity: 50%) with ad libitum access to food and water. Ex vivo electrophysiological experiments were conducted at a fixed period during the light phase in a genotype experimenter - blind approach. Diet Wild-type (wt), APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4 mice were housed in genotype-specific cages and provided ad libitum access to either a control diet or a Western diet. The control standard diet (A03, Safe, Augy, France) contained: 21% protein, 5% vegetable fat, 4% sucrose, and provided 3.4 kcal/g. The Western diet (TD.88137, Envigo Teklad, UK) was formulated to mimic human dietary patterns associated with metabolic dysfunction. It contained: 17% protein, 21% animal fat, 34% sucrose, 0.2% cholesterol, and provided 4.5 kcal/g. The diet was enriched in high-fructose corn syrup, saturated fats, and low fiber, with reduced micronutrient density and elevated milk protein. Dietary protocols were as follows: Mice in the control diet group received the standard diet continuously from birth until experimental evaluation. Mice in the Western diet group were maintained on the control diet until 5 months of age, after which the Western diet was introduced: For animals evaluated at 7 months, the Western diet was administered for 2 months (from 5 to 7 months of age), based on prior evidence that short-term Western diet exposure increases oxidative stress and alters metabolic markers in APP/PS1 models ( 33 ). For animals evaluated at 11 months, the Western diet was administered for 6 months (from 5 to 11 months of age), following studies showing that longer-term Western diet impairs cognition and promotes Aβ-related pathology in AD rodent models ( 34 ). Body weight was routinely monitored throughout the dietary intervention period to assess metabolic impact and ensure animal well-being. Slice preparation Brain hippocampal slices were obtained from 5, 7, 9 and 11 month-old wt, APP/PS1, APOE-ε4 and APP/PS1/APOE-ε4 mice, as described previously ( 10 , 14 , 35 ). Animals were anesthetized with isoflurane and the brain rapidly removed and placed in ice-cold oxygenated artificial cerebrospinal fluid (aCSF) solution continuously gassed with carbogen (95% O 2 and 5% CO 2 ) containing the following (in m M ): 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO 3 , 10 glucose, 1.3 MgCl 2 , 2 CaCl 2 , (pH = 7.3–7.4; 305–310 mOsmol/kg). A block of tissue containing the hippocampus was extracted and sliced with a VT1200S vibratome (Leica VT1200S, Leica Biosystems, Nussloch, Germany). Acute transverse slices (350 µm thick) of the dorsal hippocampus were obtained by sectioning the brain at ~ 45° from the coronal plane. The slices were transferred to a submersion recovery chamber with oxygenated aCSF at 33°C for 30 min and afterwards allowed to cool to room temperature and rest for 60 min minimum before experimentation. Following recovery period, hippocampal slices were transferred to a recording chamber installed on a BX50 fluorescence microscope (Olympus, Tokio, Japan), and held in place by a nylon mesh completely submerged and continuously perfused with gassed aCSF solution at a constant flow (3 mL/min) and temperature (32–33°C). Electrophysiology Borosilicate glass (GC150F-7.5, Harvard Apparatus, Holliston, MA) capillaries, enclosing the recording microelectrodes, were pulled on a PP-83 vertical puller (Narishige, Tokyo, Japan) and the resulting pipettes filled with aCSF (series resistance 3–5 MΩ). The CA3-CA1 hippocampal areas were identified with differential interference contrast light microscopy with a 4x Plan Achromat objective (Olympus). Field-excitatory postsynaptic potentials (fEPSPs) were evoked by orthodromic stimulation (100 ms duration) of afferent CA3 Schaffer collaterals using a concentric bipolar tungsten electrode (CBARC75, FHC, Bowdoin, USA) placed in the proximal CA1 region, > 200 µm away from the extracellular recording electrodes, located in the stratum radiatum of the distal CA1 area, close to the subiculum. To assess basal synaptic transmission efficiency, an input/output protocol was used where synaptic fEPSPs were evoked at a constant rate of 0.03 Hz stimulation of Schaffer collaterals (1 stimuli at 30 s intervals) using incremental 1V stimulation intensities (0-10V) and the resulting fEPSPs slope measured as a function of stimulus intensity. The fEPSPs slope was calculated as a linear fit of the rising phase, between time points set in the baseline period and corresponding to 20% and 60% of the peak amplitude. Data from three consecutive fEPSPs were collected for each stimulation intensity. To analyze pre-synaptic activity, we performed a paired-pulse protocol consisting in two consecutive stimuli separated by 50 ms, delivered every 30 s. The paired-pulse ratio (PPR) between the slopes of the two consecutive fEPSPs (fEPSP2/fEPSP1) was quantified. LTP experiments were done as previously ( 10 , 11 , 14 ). Briefly, fEPSPs were evoked at a constant rate of 0.03 Hz with the stimulus intensity set at 30–40% of the maximum amplitude without triggering population spikes. After obtaining a stable baseline for at least 20 min ( 60 min. The change in the slope of the fEPSP was evaluated 50–60 min post-HFS and normalized to the slope measured during the 10 min immediately before HFS. Post-tetanic potentiation (PTP) was assessed as the average fEPSPs slope obtained in the first 3 min after LTP induction. Electrophysiological recordings of the NMDAR-component of fEPSPs (NMDAR-fEPSPs) were done as previously ( 10 , 14 , 36 ). Briefly, the NMDAR contribution was extracted from global fEPSPs using picrotoxin (100 µM), NBQX (10 µM) and low external Mg 2+ concentration (0.2 mM) in the perfused aCSF, to block GABA receptors, AMPA/kainate receptors and remove the NMDAR Mg 2+ channel block, respectively. In some experiments, d -serine (50 µM) was directly applied in the perfused aCSF, immediately after the baseline period for NMDAR-fEPSPs and 20 min before recording input/output and LTP experiments, and then continuously present thorough the experiment. Data were acquired using a Multiclamp 700A amplifier (Molecular Devices, Sunnyvale, CA) controlled with pCLAMP 10 software (Molecular Devices) on current-clamp mode. Recordings were filtered at 2 kHz and digitized at 10 kHz using a Digidata 1322A digitizer interface (Axon Instruments, Inc.) and continuously stored on a personal computer. Data were collected and analyzed online and offline, respectively, using Clampfit from pCLAMP 10 software. Measurement of Amino Acids in Hippocampal Extracellular medium For the simultaneous measurement of d -serine, l -serine and glycine, a laser-induced fluorescence capillary electrophoresis detection method was employed as previously ( 14 , 36 , 37 ). Briefly, brain hippocampal transverse 350 µm slices obtained from 7-month-old wt, APP/PS1, APOE-ε4 and APP/PS1/APOE-ε4 mice were transferred to a submersion recovery chamber with oxygenated aCSF at 33°C for 45 min. Extracellular medium was quickly removed, frozen using liquid nitrogen and stored at -80°C. Extracellular levels of d -serine, l -serine and glycine were then determined. Briefly, pooled slices were deproteinized by addition of cold trichloroacetic acid (TCA) to a 4% final concentration. The suspension was centrifuged at 16,800 g for 10 min to pellet the protein content used for protein quantification. TCA was then removed from the supernatant with water-saturated diethyl ether and stored at -80°C. Samples were analyzed with a commercial laser-induced fluorescence capillary electrophoresis (CE-LIF) (CE: Beckman Coulter (Brea, California, US), P/ACE MDQ; LIF: Picometrics (Labège, France)), LIF-UV-02, 410 nm 20 mW) as follows: samples were processed for micellar CE-LIF and were fluorescently derivatized at RT for 60 min with napthalene-2,3-dicarboxaldehyde (NDA) before being analyzed by CE using a hydroxypropyl-b-cyclodextrin (HP-b-CD) based chiral separation buffer. All electropherograms data were collected and analyzed using Karat 32 software v8.0 (Beckman Coulter, France). The amounts of d -serine, l -serine and glycine were normalized to the protein content determined from pooled hippocampal slices by the Lowry method using the BCA protein Pierce assay (ThermoScientific, CA, USA) assay with bovine serum albumin (BSA) as a standard. The quantity of d -serine, l -serine and glycine in the samples was determined from a standardized curve while peak identification was made according the retention time of reference standards and by spiking the fraction with the amino acid. Drugs and chemicals Stock solutions were made and diluted with appropriate solvent before bath application. Drugs used were d -serine, l -serine, glycine (50 µM, Sigma-Aldrich, Merck, Germany), NMDA-R antagonist APV/AP-5 (10 µM, Tocris Bioscience, UK), AMPA and kainate receptors antagonist NBQX (10 µM, Tocris Bioscience), GABA A R selective antagonist picrotoxin (100 µM, Tocris Bioscience). Unless stated otherwise all remaining saline medium components and reagents were purchased from Sigma-Aldrich. Data collection and statistical analyses No statistical method was used to predetermine sample size. Sample size was chosen based on prior experience for each experiment, to yield adequate power to detect specific effects. To avoid possible bias, data collection and analysis was performed blind. Data are expressed as mean ± SEM of the n number of independent experimental units (with N number of animals and n number of slices). All data were analyzed using GraphPad Prism software (Versions 5.0 and 8.0, GraphPad, USA). Data were first screened for a Gaussian distribution with Kolmogorov-Smirnov test: normal distributed data with one independent variable (e.g. genotype) was analyzed using one-way ANOVA followed by Dunnett’s or Tukey’s parametric post hoc tests for multiple-comparisons or two-tailed t-test for dual-comparisons; normal distributed data with two or more independent variables (e.g. genotype, voltage) was analyzed using two-way ANOVA followed by Bonferroni’s multiple-comparison parametric post hoc test; non-normal distributed data was analyzed by Dunn’s multiple-comparison non-parametric post hoc test. The significance level was set at a 95% confidence level with *p < 0.05. Results Hippocampal Basal Synaptic Transmission Is Impaired in APP/PS1/APOE-ɛ4 Mice The cortico-hippocampal circuitry, particularly the glutamatergic synapses between CA3 and CA1 regions, plays a central role in hippocampal-dependent memory processing ( 38 ). Disruption or loss of these synapses contributes to explicit memory impairments, a hallmark early cognitive deficit in AD ( 3 , 4 ). To investigate whether basal synaptic transmission is influenced by the APOE-ɛ4 genotype in the context of AD, we crossed APPswe/PS1dE9 mice - a widely used model of familial (early-onset) AD ( 25 ), with APOE-ɛ4 knock-in (APOE-ɛ4-ki) mice, which carry the most significant genetic risk factor for sporadic (late-onset) AD ( 24 ). We generated four mouse lines: wt, APP/PS1, APOE-ɛ4, and APP/PS1/APOE-ɛ4, and evaluated hippocampal basal synaptic transmission at 5, 7, 9, and 11 months (Fig. 1 a-d). Synaptic transmission at CA3-CA1 synapses was assessed using an input/output (I/O) protocol, measuring the slope of the field excitatory postsynaptic potentials (fEPSPs), which reflects excitatory transmission primarily mediated by AMPA and kainate receptors. In wt mice, input/output (I/O) relationships remained stable across ages, at 5 (Fig. 1 a), 7 (Fig. 1 b), 9 (Fig. 1 c), and 11 months (Fig. 1 d) - with the complete data summarized in Fig. 1 f. Across the evaluation period, APOE-ε4 mice exhibited mild but non-significant reductions in synaptic transmission, while APP/PS1 mice showed transient significant deficits at 7 months (Fig. 1 c and 1 f, 0.48 ± 0.04 vs wt 0.66 ± 0.07 mV/ms at 10 V stimulation, n = 17, p < 0.05) that were not sustained at 9 or 11 months - findings consistent with previous reports on both APPswe/PS1dE9 and APOE-ɛ4-ki mice ( 7 , 39 , 40 ). In contrast, APP/PS1/APOE-ɛ4 mice exhibited significant deficits in basal synaptic transmission beginning at 7 months (Fig. 1 c and 1 f, 0.46 ± 0.04 vs wt 0.66 ± 0.07 mV/ms at 10 V stimulation, n = 17, p < 0.05), which became more pronounced at 9 months (Fig. 1 d and Fig. 1 f, 0.43 ± 0.05 vs wt 0.74 ± 0.07 mV/ms at 10 V stimulation, n = 15, p < 0.01) and 11 months (Fig. 1 e and 1 f, 0.34 ± 0.05 vs wt 0.63 ± 0.10 mV/ms at 10 V stimulation, n = 9, p < 0.01). These synaptic impairments were unlikely to be caused by changes in presynaptic release probability, as the paired-pulse ratio remained stable across genotypes and ages, with values consistently above 1.5, indicating intact presynaptic function and a low basal release probability typical of CA3-CA1 synapses (Fig. 1 g). Together, these results suggest that the synergistic interaction between the APP/PS1 and APOE-ɛ4 genotypes, but not either genotype alone, drives progressive basal synaptic transmission dysfunction from 7 months onward. APOE-ɛ4 Genotype Exacerbates Hippocampal Synaptic Plasticity Deficits in APP/PS1 Mice Early synaptic plasticity dysfunction is a hallmark of AD, with deficits in CA3-CA1 activity dependent long-term potentiation (LTP) observed in various AD models, including APP/PS1 mice ( 39 , 41 ). Although APOE-ɛ4 has also been linked with synaptic dysfunction ( 26 – 28 ), its specific impact on LTP deficits in AD models remains incompletely characterized. To address this, we recorded LTP in acute hippocampal slices from wild-type (wt), APP/PS1, APOE-ɛ4 knock-in, and APP/PS1/APOE-ɛ4 mice at 5, 7, 9, and 11 months of age. LTP was induced at CA3-CA1 synapses using a 100 Hz high-frequency stimulation (HFS) protocol applied three times to the Schaffer collaterals, and synaptic potentiation was considered when the fEPSPs slopes measured in between 50 to 60 minutes were increased (Fig. 2 a). Our data indicate that both wt and APOE-ɛ4 mice exhibited stable LTP across all time points, in contrast to earlier studies reporting LTP deficits in APOE-ɛ4 knock-in models ( 26 , 40 , 42 ). In APP/PS1 mice, however, significant LTP deficits emerged at 9 months (Fig. 2 c and 2 f, 140.58 ± 4.00% vs wt 155.54 ± 2.33%, n = 9, p < 0.05), and became more pronounced at 11 months (Fig. 2 d and 2 f, 133.02 ± 1.72% vs wt 152.97 ± 2.36%, n = 10, p < 0.01), consistent with previous reports in the APPswe/PS1dE9 AD model ( 43 – 47 ). Importantly, APP/PS1/APOE-ɛ4 mice exhibited a significantly greater reduction in LTP compared to APP/PS1 alone, as reflected by a marked reduction at 9 months (Fig. 2 c and 2 f, 128.39 ± 2.00% vs wt 155.54 ± 2.33%, n = 18, p < 0.001), which declined even further at 11 months (Fig. 2 d and 2 f, 120.41 ± 4.30% vs wt 155.54 ± 2.33%, n = 8, p < 0.0001). These findings demonstrate that the APOE-ɛ4 genotype significantly exacerbates synaptic plasticity deficits in APP/PS1 mice, supporting a synergistic interaction between familial (APP/PS1) and sporadic (APOE-ɛ4) genetic risk factors in the progression of hippocampal synaptic dysfunction in late-onset AD. D-Serine Rescues Impaired NMDAR-Mediated Synaptic Plasticity in APP/PS1/APOE-ɛ4 Mice LTP depends on the activation of synaptic NMDA receptors (NMDARs), and disruptions in NMDAR function are thought to contribute to early synaptic deficits in AD. Previous studies have shown that Aβ and its derivatives directly reduce synaptic NMDAR activity, a phenomenon also observed in AD patients and animal models ( 48 – 51 ). Additionally, APOE-ɛ4 has been implicated in altered regulation of synaptic NMDAR regulation in AD ( 26 , 52 ). To investigate NMDAR dysfunction in our model, we recorded the NMDAR component of field excitatory postsynaptic potentials (NMDAR-fEPSPs) at CA3-CA1 synapses in 9-month-old mice, the time point when LTP deficits were first observed (see Fig. 2 d and f). Wild-type (wt) and APOE-ɛ4 mice showed comparable NMDAR-fEPSP I/O curves (Fig. 3 b). APP/PS1 mice exhibited a modest but non-significant reduction, whereas APP/PS1/APOE-ɛ4 mice displayed a significant decrease in NMDAR-fEPSP slopes (Fig. 3 b, 0.037 ± 0.004 vs wt 0.080 ± 0.015 mV/ms at 20 V stimulation, n = 9, p < 0.05;), indicating greater NMDAR dysfunction due to the APOE-ɛ4 genotype. Because d -serine - the endogenous co-agonist of synaptic NMDARs - is essential for NMDAR-dependent LTP and memory, and is known to be reduced in 3xTg-AD mice ( 10 ), we next evaluated the co-agonist binding site occupancy of synaptic NMDARs. Following 30 minutes of baseline NMDAR-fEPSP recordings, bath application of d -serine (50 µM) induced moderate and comparable increases in NMDAR-fEPSPs in both wt (Fig. 3 c, 137.85 ± 12.86% of baseline, n = 8) and APOE-ɛ4 mice (Fig. 3 c, 135.12 ± 14.71% of baseline, n = 8). These results are consistent with previous findings suggesting that NMDAR co-agonist sites at CA3-CA1 synapses are not fully saturated under basal conditions, particularly in AD models ( 10 , 13 ). In APP/PS1 mice, d -serine application resulted in a more pronounced increase in NMDAR-fEPSPs (Fig. 3 c, 163.83 ± 11.78% of baseline, n = 9), and this effect was significantly greater in APP/PS1/APOE-ɛ4 mice (Fig. 3 c, 179.23 ± 9.90%, n = 10, p < 0.05 vs wt), indicating a lower baseline occupancy of NMDAR co-agonist sites. These findings are consistent with the reduced NMDAR activity observed in APP/PS1/APOE-ɛ4 mice (Fig. 3 b) and suggest a deficiency in synaptic d -serine availability. We hypothesized that such d -serine deficits contribute to the LTP impairments seen in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice (Fig. 2 d). In support of this, LTP impairments in APP/PS1 and APP/PS1/APOE-ɛ4 mice were significantly rescued when exogenous d -serine (50 µM) was applied in the perfused aCSF (Fig. 3 d, e). d -serine enhanced LTP across all genotypes but had a particularly strong recovery effect in APP/PS1 mice (control: 140.58 ± 4.00% vs d -serine: 161.34 ± 8.87%, n = 9, p < 0.05) and even more so in APP/PS1/APOE-ɛ4 mice (control: 128.39 ± 2.00% vs d -serine: 158.93 ± 5.94%, n = 9, p < 0.01) (Fig. 3 e). These results point to reduced d -serine availability as a key mechanism underlying NMDAR hypofunction and impaired synaptic plasticity in APP/PS1/APOE-ɛ4 mice. Western diet Accelerates Synaptic Plasticity Deficits in APOE-ɛ4-carrier Mice In addition to the well-established genetic risk conferred by the APOE-ɛ4 allele, lifestyle factors-particularly dietary habits-can significantly exacerbate susceptibility to late-onset AD ( 53 ). While high-fat diets have previously been associated with hippocampal synaptic plasticity impairments ( 54 , 55 ), the impact of the more complex Western diet - characterized by high levels of saturated fats, refined sugars, synthetic additives, and reduced protein content - on hippocampal synaptic function, especially in the presence of the APOE-ɛ4 genotype, remains poorly understood. To investigate this interaction, we exposed wt, APP/PS1, APOE-ɛ4, and APP/PS1/APOE-ɛ4 mice to either a standard control diet or a custom-formulated Western diet. We then assessed basal synaptic transmission and LTP in hippocampal slices (Fig. 4 a). The Western diet was introduced at 5 months of age and maintained for 2 months, a time window previously shown to induce neuropathological alterations in AD mouse models ( 33 , 56 ). The 7-month time point was selected as it precedes the typical onset of synaptic plasticity deficits in this model (Fig. 2 c, d) ( 34 ). Interestingly, basal synaptic transmission was elevated across all genotypes on Western diet exposure compared to their respective control-diet counterparts (Fig. 4 b, c). At 7 months of age, significant increases in basal transmission were observed in wt (p < 0.05), APP/PS1 (p < 0.01), APOE-ɛ4 (p < 0.05), and APP/PS1/APOE-ɛ4 (p < 0.05) mice on the Western diet. Despite this general enhancement, APP/PS1/APOE-ɛ4 mice still displayed impaired basal synaptic transmission relative to wt mice on the same diet (0.75 ± 0.06 vs. 1.05 ± 0.09 mV/ms, n = 11, p < 0.05; Fig. 4 b, c). Moreover, APOE-ɛ4 mice fed a Western diet also exhibited synaptic deficits compared to wt mice on the same diet (0.75 ± 0.07 vs. 1.05 ± 0.09 mV/ms, n = 9, p < 0.05), a phenotype not observed under control diet conditions. These findings suggest that while Western diet intake broadly increases basal synaptic activity across genotypes, it does not normalize or reverse synaptic vulnerability in APOE-ɛ4 genotype carriers. Interestingly, the Western diet induced synaptic plasticity deficits at an earlier time point. At 7 months of age, while LTP remained intact under control diet conditions (Fig. 2 c, Fig. 4 e), significant impairments were observed in APOE-ɛ4 (131.83 ± 7.13% vs. wt 158.42 ± 4.31%, n = 9, p < 0.05) and APP/PS1/APOE-ɛ4 mice (128.70 ± 5.00% vs. wt 158.42 ± 4.31%, n = 16, p < 0.05) following Western diet intake (Fig. 4 d, e). Similar deficits were also observed at 11 months of age (data not shown), suggesting that these impairments persist beyond the early onset phase. Thus, just two months of Western diet exposure were sufficient to advance the onset of LTP deficits in APP/PS1/APOE-ɛ4 mice from 9 months (Fig. 2 d, f) to 7 months (Fig. 4 d, e), and to unmask previously absent impairments in APOE-ɛ4 mice. Notably, LTP in wt and APP/PS1 mice remained unaffected by the Western diet. These findings suggest that the Western diet selectively interacts with the APOE-ɛ4 genotype to advance and precipitate hippocampal synaptic plasticity deficits. d -Serine Restores NMDAR-Dependent Synaptic Plasticity From Deficits Present in APOE-ɛ4-carrier Mice on a Western Diet Given that d -serine effectively rescued NMDAR-dependent synaptic plasticity deficits in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice under control diet conditions (Fig. 3 ), we next investigated whether a similar d -serine deficiency was involved in the LTP impairments observed at 7 months in mice fed a Western diet (Fig. 4 ). To this end, we assessed synaptic NMDAR activity by recording the NMDAR component of field EPSPs (NMDAR-fEPSPs) using an I/O protocol in hippocampal slices from 7-month-old mice maintained on either control or Western diet (Fig. 5 b, c). Under control diet conditions, all genotypes exhibited comparable NMDAR-fEPSP I/O curves (Fig. 5 b). In contrast, Western diet (Fig. 5 a-c) led to a significant reduction in NMDAR-mediated synaptic responses in APP/PS1 (0.006 ± 0.01 mV/ms, n = 10, p < 0.05), APOE-ɛ4 (0.055 ± 0.004 mV/ms, n = 14, p < 0.01), and APP/PS1/APOE-ɛ4 mice (0.047 ± 0.004 mV/ms, n = 11, p < 0.001), relative to wt mice on the same diet (0.077 ± 0.01 mV/ms, n = 10). This contrasts with the increased basal synaptic transmission observed under Western diet in Fig. 4 b, suggesting that the previous general fEPSP enhancement is not mediated by NMDARs, but likely reflects increased AMPAR or kainate-driven excitability. These findings suggest that APOE-ɛ4 genotype carriers are particularly vulnerable to NMDAR hypofunction under Western diet conditions. To assess whether reduced d -serine availability contributes to the observed NMDAR hypofunction, we evaluated co-agonist site occupancy at synaptic NMDARs by applying exogenous d -serine (50 µM) to hippocampal slices from 7-month-old mice under either control or Western diet conditions (Fig. 5 d, e). Under control diet conditions, all genotypes responded similarly to d -serine application after 30 min, indicating comparable baseline co-agonist site occupancy. However, under Western diet exposure, d -serine elicited significantly greater increases in NMDAR-fEPSPs in APOE-ɛ4 (173.0 ± 8.0%, n = 13, p < 0.05) and APP/PS1/APOE-ɛ4 mice (182.0 ± 9.0%, n = 10, p < 0.001) relative to wt controls (143.0 ± 4.0%, n = 15). These findings suggest that Western diet reduces endogenous d -serine availability in APOE-ɛ4 carriers, thereby limiting NMDAR activation and contributing to synaptic dysfunction. To confirm whether reduced NMDAR function was associated with altered co-agonist availability, we quantified extracellular levels of d -serine, l -serine (its biosynthetic precursor), and glycine from hippocampal slice perfusates using capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) (Fig. 6a). This method enables precise, simultaneous quantification of amino acids in small volume samples, providing insights into receptor ligand dynamics ( 36 , 57 , 58 ). Under control diet conditions, extracellular concentrations of d -serine, l -serine, and glycine did not differ significantly across genotypes, indicating preserved amino acid homeostasis in the hippocampus (Fig. 6b, d, f). In contrast, Western diet exposure led to a marked reduction in d -serine and l -serine extracellular levels specifically in APP/PS1/APOE-ɛ4 mice, while glycine remained unaffected. d -serine levels in these mice dropped significantly compared to their control diet counterparts (0.057 ± 0.003 nmol/mg vs. 0.076 ± 0.005 nmol/mg, p < 0.05; Fig. 6c), as did levels of its biosynthetic precursor l -serine (1.602 ± 0.086 nmol/mg vs. 2.140 ± 0.167 nmol/mg, p < 0.05; Fig. 6e). In contrast, glycine concentrations remained stable across all genotypes and dietary conditions (Fig. 6g), suggesting that the observed NMDAR co-agonist deficiency is specific to the d -serine pathway. These results further support that Western diet selectively impairs d -serine metabolism in APP/PS1/APOE-ɛ4 mice, contributing to reduced NMDAR activation and synaptic dysfunction. Given the observed reductions in d -serine levels and d -serine-dependent NMDAR activity, we next tested whether exogenous d -serine (Fig. 7 ) could restore the impaired synaptic function observed in 7-month-old APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice fed with a Western diet (Fig. 4 ). Interestingly, d -serine application (50 µM) effectively rescued LTP impairments in both APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice fed a Western diet (Fig. 7 b). In APOE-ɛ4 mice, LTP was significantly improved following d -serine treatment (Fig. 7 c, Western diet: 131.83 ± 7.13% vs. Western diet + d -serine: 160.46 ± 6.30%, n = 9, p < 0.05;), and a similar rescue was observed in APP/PS1/APOE-ɛ4 mice (Fig. 7 c, Western diet: 128.70 ± 5.00% vs. Western diet + d -serine: 155.91 ± 4.08%, n = 10, p < 0.05). Our results show that exogenous d -serine not only rescued LTP deficits in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice under control diet conditions (Fig. 3 ), but also mitigated the synaptic plasticity impairments induced by Western diet in 7-month-old APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice (Fig. 7 ). These effects support a role for reduced d -serine availability in the synaptic deficits observed across genotypes and diet conditions, particularly in the presence of APOE-ɛ4 and Western diet. Discussion Synaptic dysfunction is recognized as a central and early feature of AD, often preceding overt amyloid plaque deposition, tau pathology, or neuronal loss ( 59 – 61 ). Reductions in hippocampal synaptic density, alterations in dendritic spine morphology, and impairments in synaptic plasticity, particularly long-term potentiation (LTP), are tightly linked to cognitive decline ( 5 , 6 , 41 , 62 ). Although transgenic mouse models have provided invaluable insights into these processes, they fall short of recapitulating the complexity of sporadic, late-onset AD, which accounts for more than 95% of AD cases ( 41 ). Notably, few models integrate both genetic and modifiable lifestyle risk factors - such as the APOE-ε4 allele and Western dietary patterns - that better reflect real-world vulnerability. To address this, we combined APOE-ε4 expression and Western diet exposure in APP/PS1 mice, providing a model that may more closely reflect the pathophysiological conditions underlying early synaptic dysfunction. Although APOE-ε4 is the strongest genetic risk factor for late-onset AD, its effects on synaptic function remain incompletely understood ( 19 , 20 ). APOE-ε4 knock-in mice show increased Aβ burden, impaired amyloidal clearance, and heightened neuroinflammation ( 63 – 65 ). Even without amyloid pathology, APOE-ε4 mice exhibit early, sex-dependent cognitive and behavioral changes ( 52 , 66 – 68 ), accompanied by reduced synaptic markers and spine density ( 69 – 71 ). However, studies of synaptic physiology in APOE-ε4 models have been inconsistent, with some reporting impaired synaptic transmission ( 72 , 73 ) and LTP ( 26 , 40 , 42 ), while others found no deficits or even enhancements ( 74 – 76 ), possibly reflecting different experimental conditions, mice strains or age. In our study, APOE-ε4 mice under control diet showed no synaptic impairment, consistent with previous reports ( 74 – 76 ). However, the combination of APOE-ε4 and APP/PS1 mutations led to progressive deficits in synaptic transmission and LTP, with impairments in synaptic transmission emerging at 7 months and LTP deficits appearing by 9 months under control diet conditions, suggesting that APOE-ε4 aggravates synaptic vulnerability in the context of amyloid pathology (Figs. 1 and 2 ). These findings highlight a synergistic interaction between APOE-ε4 and amyloidogenic pathology in the early synaptic pathogenesis of AD. Our data further reveal that the impaired synaptic plasticity observed in APP/PS1/APOE-ɛ4 mice is strongly associated with NMDAR hypofunction, likely derived from reduced availability of d -serine, the essential co-agonist at synaptic NMDARs (Fig. 3 ). These findings align with our previous work showing that d -serine supplementation restores LTP and memory in 3xTg-AD mice ( 10 ), and supports synaptic NMDAR function in other AD models ( 15 , 16 ). Notably, exogenous d -serine rescued both NMDAR-mediated responses and LTP deficits in APP/PS1 and APP/PS1/APOE-ɛ4 mice, underscoring the therapeutic potential of targeting d -serine signaling in early AD-related synaptic pathology. While high-fat diets have been shown to disrupt synaptic plasticity and cognitive performance ( 54 , 55 , 77 ), far less is known about the effects of a full Western diet, which more closely mimics modern dietary patterns and real-world risk by combining high levels of saturated fat, refined sugars, synthetic additives, and reduced protein. Epidemiological studies have increasingly linked Western diet consumption to an elevated risk of AD ( 29 , 30 , 78 ). While its long-term metabolic consequences - such as obesity, insulin resistance, and cardiovascular disease - are well documented ( 29 , 30 , 78 ), the specific mechanisms through which Western diet impacts brain function, particularly in the early stages of AD and in interaction with the APOE-ε4 genotype, remain poorly defined. In the brain, Western diet has been associated with increased Aβ accumulation, glial activation, blood-brain barrier dysfunction and neuroinflammation ( 31 , 32 ). However, its direct influence on synaptic physiology, especially under APOE-ε4-related vulnerability, is still largely unexplored. We found that just two months of Western diet intake is sufficient to precipitate significant hippocampal synaptic plasticity deficits in APOE-ε4 and APP/PS1/APOE-ε4 mice - deficits not observed under control diet conditions at this age (Fig. 4 ). This early onset of LTP impairment, alongside the induction of synaptic deficits in APOE-ε4 carriers, supports a synergistic interaction between diet and genotype, as previously suggested ( 78 ). Importantly, this occurred without affecting LTP in WT or APP/PS1 mice, highlighting a selective vulnerability of APOE-ε4 carriers. In regards to basal synaptic transmission, Western diet increased fEPSPs across all genotypes; however, APOE-ε4 carriers continued to show weaker transmission compared to wt and APP/PS1 mice (Fig. 4 ), indicating that Western diet does not normalize intrinsic genotype-dependent basal transmission vulnerability. While high-fat diets have been linked to hippocampal baseline neurotransmission impairments ( 79 , 80 ), Western diet intake, consistent with our findings, has conversely been associated with increased basal neuronal excitability in various brain regions ( 81 , 82 ). This supports a complex, multifaceted impact of Western diet on hippocampal function - particularly in APOE-ɛ4 carriers - distinct from the effects observed with more simplified high-fat diets. Notably, despite the general enhancement in fEPSPs slopes, NMDAR-mediated responses were significantly reduced in APOE-ε4, APP/PS1, and APP/PS1/APOE-ε4 mice (Fig. 5 ), suggesting that the increased basal synaptic transmission under Western diet is likely driven by AMPAR or kainate-driven excitability, not NMDARs. This selective NMDAR hypofunction, particularly in APOE-ε4 carriers, may underlie the failure to sustain synaptic plasticity. To our knowledge, this is the first evidence that Western diet alone is sufficient to induce synaptic plasticity dysfunction in APOE-ε4 carriers, where such deficits were absent under control diet conditions, and advances their onset in APP/PS1/APOE-ε4 mice. Our data further reveal that the synaptic vulnerability observed in APOE-ε4 carriers under Western diet conditions is tightly linked to reduced availability of d -serine ( 15 , 16 ). While synaptic NMDAR responses remained intact under control diet across all genotypes, Western diet exposure significantly reduced NMDAR-mediated transmission in APOE-ε4 and APP/PS1/APOE-ε4 mice (Fig. 5 ), supporting the view that these genotypes are especially susceptible to diet-induced glutamatergic disruption ( 83 – 85 ). Importantly, this NMDAR hypofunction was associated with a greater potentiation of NMDAR-fEPSPs following exogenous d -serine application, suggesting a deficit in endogenous co-agonist availability. Supporting this, CE-LIF biochemical analysis confirmed significantly reduced extracellular d -serine and its biosynthetic precursor l -serine in the hippocampus of Western diet-fed APP/PS1/APOE-ε4 mice, while glycine levels remained unchanged ( Fig. 6 ). While d -serine has been consistently shown to support cognitive function in aging-related decline ( 86 – 88 ), its role in AD remains more controversial. Across various AD models and patient cohorts, some studies have reported reduced d -serine levels and beneficial effects following supplementation ( 10 , 15 , 16 , 89 – 92 ). In contrast, others have found elevated d -serine levels linked to excitotoxicity and disease progression ( 93 – 97 ), while a few report no significant changes at all ( 98 , 99 ). These discrepancies likely reflect differences in AD mouse models, their underlying glycolytic and metabolic states, or the disease stage in patient samples. In general, d -serine appears beneficial in prodromal and early-phase AD - approximately 4–8 months in APP/PS1 mice - but may exert deleterious effects in intermediate and late disease stages ( 86 – 88 , 100 , 101 ). Here, we showed that D -serine supplementation fully rescued LTP deficits at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice (Fig. 7 ), and also restored function in older animals (9–11 months) under control diet (Fig. 3 ). This suggests that in the APP/PS1/APOE4 model, NMDAR hypofunction persists beyond early stages, potentially extending the therapeutic window for l -serine or d -serine intervention. These results align with our previous findings that both l - and d -serine levels are reduced in AD patients and in 6–7-month-old 3xTg-AD mice, and that l - and d -serine supplementation can restore synaptic plasticity and memory function in the 3xTg-AD model ( 10 ). This reduction in d -serine was linked to altered astrocytic glycolytic flux and disruption of l -serine biosynthesis, observed in both human and animal models ( 10 , 101 , 102 ). d - and l -serine reductions observed in APP/PS1/APOE-ε4 mice likely reflect a shift in astrocytic metabolism toward aerobic glycolysis, a pattern independently induced by both APOE-ε4 expression and Western diet ( 103 , 104 ). Notably, rodents exposed to high-fat and Western diets ( 104 – 108 ), as well as APOE4-expressing astrocytes ( 84 , 104 , 109 – 111 ), exhibit similarly reprogrammed metabolic profiles - marked by decreased oxidative metabolism and reduced biosynthetic capacity - suggesting a shared vulnerability that may converge on serine metabolism. These combined stressors likely divert glycolytic flux away from the phosphorylated pathway of l -serine synthesis ( 102 , 104 ), thereby diminishing NMDAR co-agonist availability and compromising astrocyte-neuron metabolic coupling ( 10 , 112 , 113 ). Interestingly, while d -serine has therapeutic potential, its clinical use is limited by nephrotoxicity concerns, particularly in rodents ( 114 ). l -serine, by contrast, shares neuroprotective effects in AD and aging - supporting protein homeostasis, anti-inflammatory responses, and synaptic resilience - with a more favorable safety profile ( 10 , 89 , 115 ). Thus, targeting astrocytic l -serine biosynthesis may offer a safer route for therapeutic intervention in APOE-ε4 carriers. Together, these results highlight the convergence of genetic (APOE-ε4) and environmental (Western diet) risk factors on d -serine/NMDAR signaling as a key mechanistic pathway in early synaptic dysfunction in AD, and a potential target for therapeutic strategies. Conclusion Our study provides new mechanistic insight into how the APOE-ε4 genotype and Western diet synergistically aggravate and accelerate hippocampal synaptic dysfunction through disruption of d -serine/NMDAR signaling. These findings underscore the necessity of considering both genetic and lifestyle risk factors in modeling and understanding early late-onset AD pathophysiology. Furthermore, they highlight astrocytic serine biosynthesis as a metabolically sensitive and modifiable pathway with therapeutic relevance. Targeting l - and d -serine metabolism may offer a safer and effective early intervention approach, especially for individuals carrying the APOE-ε4 allele. Abbreviations AD Alzheimer’s disease APOE Apolipoprotein E APOE-ɛ4 Apolipoprotein E ɛ4 allele APP/PS1 Amyloid precursor protein-Presenilin-1 Aβ Amyloid-beta CE-LIF Capillary electrophoresis with laser-induced fluorescence CNS Central nervous system d -ser d -serine l -ser l -serine fEPSP Field excitatory postsynaptic potential HFS High-frequency stimulation I/O Input-output KI Knock-in LTP Long-term potentiation NMDAR N-methyl-D-aspartate receptor NMDAR-fEPSP NMDAR-mediated field excitatory postsynaptic potential PPF Paired-pulse facilitation SC Schaffer collaterals WD Western diet wt Wild-type. Declarations Funding This study was funded by INSERM (to P.A., O.S.H.R.); CNRS (to P.A., O.S.H.R.); the Agence Nationale de la Recherche/ EU Joint Programme - Neurodegenerative Disease Research (JPND) (JPND DACAPO-AD: RPB16004GGA) and Vaincre Alzheimer (RAK20002GGA; to O.S.H.R., M.M. and O.A.). This work benefited from the support of various facilities granted by INSERM and LabEX BRAIN ANR-10-LABX-43. Author Contribution M.M. performed the experiments, analyzed the data, and drafted the manuscript. O.A., M.I., and L.B.A. assisted with CE-LIF experiments and their analysis. C.P. assisted with additional experiments. H.E. was responsible for mouse breeding and genotyping, and L.D. oversaw animal care. O.S.H.R. and P.A. supervised the project, contributed to data interpretation, and provided manuscript review and editing. All authors reviewed and approved the final version of the manuscript. Acknowledgement The authors gratefully acknowledge the staff of the Neurocentre Magendie Animal Facility and the PUMA (Magendie Unified Platforms) for their dedicated support in animal care and experimental logistics. We also thank the technical team in Oliet’s lab for their valuable assistance throughout the project. We are particularly grateful to all past and present members of the Oliet lab for their insightful discussions and continuous support. Finally, we thank the entire JPND DACAPO-AD consortium for all the fruitful and stimulating scientific exchanges. References Querfurth HW, Laferla FM. Alzheimer’s Disease. N Engl J Med. 2010;362:329–44. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):1–14. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Sci (80-). 2002;298(5594):789–91. Arendt T. Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol. 2009;118(1):167–79. Scheff SW, Price DA, Schmitt FA, Mufson EJ. 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Biomedicines. 2023;11(8). Additional Declarations No competing interests reported. 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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-7320776","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":502414097,"identity":"9e2c0146-a456-494a-8c41-d05e6e967821","order_by":0,"name":"Marco Matos","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYPACCwaGGxCWHIg48ICwFgmQFsaGAwwMxmAtCaRoSWwA8fFp0W0/+/DDBwYJOb7bzccff6i4lz4/7PBDoC12croN2LWYnUk3lpzBIGEseedYYsOBM8W5G2+nGQC1JBubHcCh5UAaGzMPg0Tihhs5hg0H2xJyN85OAGk5kLgNl5bzz8Ba6jfcyP/YcPBfQrrh7PQP+LXcgNiSYHAjh7HhYENCgrx0DgFbbjxjlpxhIGE4884xwxlnjiUYbpDOKTiQYIDHL+fTGD98qLCRB4bYgw8VNQny8rPTNwNF7ORwaYEAA2T2AXQRgkC+gRTVo2AUjIJRMBIAAPPPZ0+Soc0XAAAAAElFTkSuQmCC","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":true,"prefix":"","firstName":"Marco","middleName":"","lastName":"Matos","suffix":""},{"id":502414103,"identity":"9878a165-cbed-4d38-b024-c63a1f840613","order_by":1,"name":"Aymeric Oliveira","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Aymeric","middleName":"","lastName":"Oliveira","suffix":""},{"id":502414108,"identity":"bf46cbd2-98e7-4b9a-b138-b59421b0fcaf","order_by":2,"name":"Isabelle Matias","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Isabelle","middleName":"","lastName":"Matias","suffix":""},{"id":502414109,"identity":"5af23085-7e34-48cb-9446-d6b50eaa170b","order_by":3,"name":"Anna Le Boulch","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Le","lastName":"Boulch","suffix":""},{"id":502414110,"identity":"5def0487-616f-49e1-8bb4-06aa4e1952c4","order_by":4,"name":"Phillipe Ciofi","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Phillipe","middleName":"","lastName":"Ciofi","suffix":""},{"id":502414111,"identity":"ddff399d-3513-4461-a234-d8984e756826","order_by":5,"name":"Lionel Dupuy","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Lionel","middleName":"","lastName":"Dupuy","suffix":""},{"id":502414112,"identity":"07389385-04ec-4e28-9272-609ebcc3ba62","order_by":6,"name":"Elizabeth Huc","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Elizabeth","middleName":"","lastName":"Huc","suffix":""},{"id":502414116,"identity":"44f842b4-6d8f-412a-8dbd-6735c9e9a667","order_by":7,"name":"Stéphane Henri Richard Oliet","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Stéphane","middleName":"Henri Richard","lastName":"Oliet","suffix":""},{"id":502414118,"identity":"54c5476d-a87b-47cc-a731-0e7a5055cbfb","order_by":8,"name":"Aude Panatier","email":"","orcid":"","institution":"Univ. Bordeaux, INSERM, Neurocentre Magendie","correspondingAuthor":false,"prefix":"","firstName":"Aude","middleName":"","lastName":"Panatier","suffix":""}],"badges":[],"createdAt":"2025-08-07 16:38:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7320776/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7320776/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13195-026-01992-y","type":"published","date":"2026-02-25T15:59:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90047575,"identity":"a8496eed-4e24-449f-a11c-c69c2b623cd3","added_by":"auto","created_at":"2025-08-27 18:41:20","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":906989,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAPOE-ɛ4 exacerbates age-dependent deficits in basal synaptic transmission in APP/PS1 mice.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Experimental setup: acute hippocampal slices were prepared from wild-type (wt, green), APP/PS1 (purple), APOE-ɛ4 (blue), and APP/PS1/APOE-ɛ4 (red) mice aged 5, 7, 9, and 11 months, all maintained on a control diet. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region along the Schaffer collateral pathway, using a stimulating electrode in proximal CA1 and a recording electrode in distal CA1. \u003cstrong\u003eb-e\u003c/strong\u003e. Input/output (I/O) curves of fEPSP slope versus stimulus intensity for each genotype at 5 (b), 7 (c), 9 (d), and 11 (e) months of age. Scatter plots (left) show average responses across stimulus voltages; representative traces (top) and bar graphs at 10 V stimulation (right) summarize the data. APP/PS1/APOE-ɛ4 mice show emerging deficits by 7 months, with progressive worsening at 9 and 11 months. \u003cstrong\u003ef.\u003c/strong\u003e Summary bar graph of fEPSP slopes at 10 V across ages and genotypes. While APP/PS1 mice show moderate synaptic transmission decline with age, APP/PS1/APOE-ɛ4 mice exhibit a significantly greater and earlier impairment. \u003cstrong\u003eg.\u003c/strong\u003e Paired-pulse ratio (PPR, fEPSP2/fEPSP1) shows no significant changes across genotypes or ages, indicating that presynaptic release probability is not altered. (*p \u0026lt; 0.05, **p \u0026lt; 0.01; 2-way ANOVA for scatter plots and 1-way ANOVA for bar graphs, followed by Tukey’s post hoc test.)\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/7b59ef6657e112dd8c66ee25.jpeg"},{"id":90047647,"identity":"01c37244-9fb2-43b1-a28c-7887da37654f","added_by":"auto","created_at":"2025-08-27 18:49:20","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":850802,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAPOE-ɛ4 aggravates age-related synaptic plasticity deficits on APP/PS1 mice.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Experimental setup: acute hippocampal slices were obtained from wild-type (wt, green), APP/PS1 (purple), APOE-ɛ4 (blue), and APP/PS1/APOE-ɛ4 (red) mice aged 5, 7, 9, and 11 months, all maintained on a control diet. LTP was induced using a high-frequency stimulation (HFS) protocol at CA3-CA1 synapses. Stimulating and recording electrodes were placed in proximal and distal CA1, respectively. \u003cstrong\u003eb–e\u003c/strong\u003e. Time-course plots of fEPSP slope changes following HFS-LTP induction for each genotype at 5 (b), 7 (c), 9 (d), and 11 (e) months. Representative traces (top) show pre- and post-HFS responses; summary bar graphs (right) present mean potentiation levels 40–60 min post-HFS. LTP remained intact across genotypes at 5 and 7 months but was significantly reduced in APP/PS1 and further impaired in APP/PS1/APOE-ɛ4 mice from 9 months onward. \u003cstrong\u003ef.\u003c/strong\u003e Summary bar graph showing progressive LTP decline with age, with APP/PS1/APOE-ɛ4 mice exhibiting the most severe impairments. (*p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001; 2-way ANOVA for time-course data and 1-way ANOVA for bar graphs, followed by Tukey’s post hoc test.)\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/5cd9803dea07861bef96b505.jpeg"},{"id":90046746,"identity":"92c56a90-5de8-4543-8bdd-6c454f6e6e61","added_by":"auto","created_at":"2025-08-27 18:33:20","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":659418,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ed-serine rescues NMDAR function and synaptic plasticity deficits in APP/PS1 and APP/PS1/APOE-ɛ4 mice.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Experimental setup: hippocampal slices from 9-month-old wild-type (wt, green), APP/PS1 (purple), APOE-ɛ4 (blue), and APP/PS1/APOE-ɛ4 (red) mice (control diet) were used to assess NMDAR function and LTP at CA3-CA1 synapses, with or without d-serine application (50 μM). \u003cstrong\u003eb.\u003c/strong\u003eInput/output (I/O) curves of NMDAR-mediated fEPSPs across genotypes. APP/PS1/APOE-ɛ4 mice exhibited a significant reduction in NMDAR responses compared to wt. Representative traces (top), I/O scatter plot (left), and summary bar graph at 20 V (right) are shown. \u003cstrong\u003ec.\u003c/strong\u003e NMDAR co-agonist occupancy assessed by d-serine-induced potentiation of fEPSPs. d-serine produced significantly larger responses in APP/PS1/APOE-ɛ4 slices, indicating reduced baseline occupancy. \u003cstrong\u003ed.\u003c/strong\u003e Effect of d-serine on LTP: time-course graphs (left), representative traces (top), and summary bar graphs (right) show that d-serine restored LTP in APP/PS1 and APP/PS1/APOE-ɛ4 mice. \u003cstrong\u003ee.\u003c/strong\u003e Summary bar graph comparing potentiation levels in control (–) vs. d-serine-treated (+) slices. D-serine fully rescued synaptic plasticity deficits in both APP/PS1 and APP/PS1/APOE-ɛ4 groups. (*p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001; 2-way ANOVA for time-course data and 1-way ANOVA for bar graphs, followed by Tukey’s post hoc test.)\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/5e1382e63a978d45eb4ad2e0.jpeg"},{"id":90046743,"identity":"d56201d3-1049-4afd-a6cc-826704e075c0","added_by":"auto","created_at":"2025-08-27 18:33:20","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":704017,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWestern diet accelerates synaptic plasticity deficits in APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Experimental setup: 5-month-old wt (green), APP/PS1 (purple), APOE-ɛ4 (blue), and APP/PS1/APOE-ɛ4 (red) mice were fed a Western diet or maintained on a control diet for 2 months. At 7 months, acute hippocampal slices were used to assess basal synaptic transmission and LTP at CA3-CA1 synapses. \u003cstrong\u003eb.\u003c/strong\u003e I/O curves of fEPSP slopes for Western diet-fed 7-month-old mice. All genotypes showed increased basal synaptic output. \u003cstrong\u003ec.\u003c/strong\u003e Comparative bar graph of fEPSP slopes at 10 V stimulation between Western diet -fed and control diet-fed groups reveals that Western diet enhances basal transmission without altering the genotype-specific pattern of impairment. \u003cstrong\u003ed.\u003c/strong\u003e LTP recordings after HFS in Western diet-fed mice. Time-course graphs (left), representative traces (top), and summary bar graphs (right) show that APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice exhibit significant LTP deficits under Western diet but not control diet conditions. \u003cstrong\u003ee.\u003c/strong\u003e Comparative summary of LTP levels between Western diet - and control diet-fed mice across genotypes. (*p \u0026lt; 0.05, **p \u0026lt; 0.01; 2-way ANOVA for time-course data, 1-way ANOVA for bar graphs; Tukey’s post hoc test.)\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/0db166b0804186dd6af2d2bd.jpeg"},{"id":90046745,"identity":"85e84ed1-711c-45f0-a746-44a73e9c7ccb","added_by":"auto","created_at":"2025-08-27 18:33:20","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":725169,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ed-serine occupancy at synaptic NMDARs is reduced in APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice following Western diet.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Experimental setup: 5-month-old wt (green), APP/PS1 (purple), APOE-ɛ4 (blue), and APP/PS1/APOE-ɛ4 (red) mice were fed a Western diet or maintained on a control diet for 2 months. At 7 months, hippocampal slices were prepared for CA3-CA1 fEPSP recordings with or without d-serine (50 μM) application. \u003cstrong\u003eb-c.\u003c/strong\u003e NMDAR-fEPSP input/output (I/O) curves from control diet (\u003cstrong\u003eb\u003c/strong\u003e) or Western diet -fed (\u003cstrong\u003ec\u003c/strong\u003e) mice. Western diet significantly reduced NMDAR-mediated transmission in APP/PS1, APOE-ɛ4, and APP/PS1/APOE-ɛ4 mice. \u003cstrong\u003ed-e\u003c/strong\u003e. Potentiation of NMDAR-fEPSPs by d-serine under control diet (\u003cstrong\u003ed\u003c/strong\u003e) or Western diet (\u003cstrong\u003ee\u003c/strong\u003e). Time-course graphs, representative traces, and bar graphs show that d-serine responses were significantly enhanced in APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice under Western diet, indicating reduced endogenous occupancy of the NMDAR co-agonist site. (*p \u0026lt; 0.05, **p \u0026lt; 0.01; 2-way ANOVA for time-course data, 1-way ANOVA for bar graphs; Tukey’s post hoc test.)\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/d0d4a0ac8eee957706ea6f48.jpeg"},{"id":90046742,"identity":"4cb9e972-c94a-4224-9ab7-b671dca1dfc4","added_by":"auto","created_at":"2025-08-27 18:33:20","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":171270,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWestern diet reduces extracellular hippocampal levels of d-serine and l-serine in APP/PS1/APOE-ɛ4 mice.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea. \u003c/strong\u003eExperimental setup: 5-month-old wild-type (wt, green), APP/PS1 (purple), APOE-ɛ4 (blue), and APP/PS1/APOE-ɛ4 (red) mice were fed a Western diet or maintained on a control diet for 2 months. At 7 months, acute hippocampal slices were incubated in aCSF, and extracellular amino acid concentrations were quantified using capillary electrophoresis with laser-induced fluorescence (CE-LIF). \u003cstrong\u003eb–g\u003c/strong\u003e. Extracellular concentrations of d-serine (b, c), l-serine (d, e), and glycine (f, g) under control diet (top panels: b, d, f) and Western diet (bottom panels: c, e, g). Under Western diet conditions, APP/PS1/APOE-ɛ4 mice exhibited significantly reduced d-serine (c) and l-serine (e) levels compared to other genotypes, while glycine levels remained unchanged (g). No significant differences were detected under control diet conditions. (*p \u0026lt; 0.05; 1-way ANOVA with Tukey’s post hoc test.)\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/dc26682b8d0f62e00a2e4891.png"},{"id":90046748,"identity":"4b70a149-0555-400b-a822-a4058b93c38f","added_by":"auto","created_at":"2025-08-27 18:33:20","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":449738,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ed-serine rescues synaptic plasticity deficits at CA3-CA1 synapses in APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice fed a Western diet.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Diagram of the experimental setup: 5-month-old wild-type (WT, green), APP/PS1 (purple), APOE-ɛ4 (blue), and APP/PS1/APOE-ɛ4 (red) mice were fed a Western diet or maintained on a control diet for 2 months prior to acute hippocampal slice preparation for fEPSP recordings at CA3-CA1 synapses, with or without bath-applied d-serine (50 μM). \u003cstrong\u003eb\u003c/strong\u003e. Average fEPSP slopes before (1) and after (2) high-frequency stimulation (HFS) LTP induction in 7-month-old Western diet-fed mice. Time-course plots (left), representative traces (top), and comparative bar graphs (right) show that acute d-serine application restores LTP in both APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice (\u003cstrong\u003ec\u003c/strong\u003e). (*, comparison with line-matched condition. *p \u0026lt; 0.05, with 2-way ANOVA and 1-way ANOVA for time-course and bar graphs, respectively, followed by Tukey’s post hoc test.)\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/70e860532d3cbac32b19beb0.jpeg"},{"id":103766580,"identity":"6affdf45-21d2-4eff-8ed7-90cc489f2666","added_by":"auto","created_at":"2026-03-02 16:15:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5683452,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7320776/v1/a4a94552-83de-48e4-8cba-9b0f6dc0ef70.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption","fulltext":[{"header":"Background","content":"\u003cp\u003eAlzheimer\u0026rsquo;s disease (AD) is the most common chronic neurodegenerative disorder, clinically characterized by a progressive decline of cognitive functions such as learning and memory, ultimately leading to severe dementia and functional decline. It is estimated that over 50\u0026nbsp;million people worldwide are affected by AD, with projections suggesting this number will double by 2040 (source: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.alz.co.uk\u003c/span\u003e\u003c/span\u003e). Although the exact etiology remains debated, hallmark pathological features include impaired glucose metabolism, followed by accumulation of extracellular amyloid-beta (A\u0026beta;) plaques, intracellular neurofibrillary tangles, and inflammation - ultimately culminating in neuronal impairment and death (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e). Synaptic dysfunction, particularly in the limbic cortex, is believed to play a central role in disease progression. Memory impairments in AD are closely associated with reduced synaptic density and efficacy, especially in the hippocampus, where glutamatergic synapses are highly vulnerable (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eSeveral studies have reported early synaptic deficits in AD, notably at hippocampal glutamatergic synapses, including reduced dendritic spine density and impaired long-term potentiation (LTP), a key form of synaptic plasticity critical for learning and memory and among the earliest functions disrupted in AD (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). LTP at CA3-CA1 synapses is primarily mediated by postsynaptic NMDA receptor activation, which initiates intracellular signaling cascades that enhance synaptic strength and connectivity (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). Its early disruption in AD underscores the vulnerability of these synapses and highlights LTP impairment as a key pathological hallmark. We have previously shown that deficits in synaptic plasticity and memory in the triple-transgenic mouse model (3xTg-AD) are linked to reduced astrocytic glycolysis and therefore reduced biosynthesis of \u003cspan class=\"SmallCaps\"\u003el\u003c/span\u003e-serine and \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e). As an essential co-agonist of synaptic NMDA receptors (NMDARs) at hippocampal CA3-CA1 synapses (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e), \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine plays a key role in NMDAR-dependent synaptic plasticity. Accordingly, reduced \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine availability has been consistently associated with impaired NMDAR function and cognitive decline in both AD models (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e) and during normal aging (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWhile most transgenic models of AD reflect familial (early-onset) forms, which account for only 5\u0026ndash;10% of cases (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e), the majority of AD cases are sporadic and late-onset. The strongest genetic risk factor for late-onset AD is the presence of the apolipoprotein E ɛ4 allele (APOE-ɛ4) (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e), which increases the risk of AD by 3- to 15-fold (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e). Though the exact mechanisms by which APOE-ɛ4 promotes AD are still under investigation, evidence suggests it contributes to increased A\u0026beta; deposition, cerebrovascular dysfunction, and altered cerebral metabolism (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e). In APOE-\u0026epsilon;4 knock-in mice, impairments in synaptic plasticity, reductions in dendritic spine density, and increased neuronal hyperexcitability have been observed, further implicating APOE-\u0026epsilon;4 in AD-related synaptic vulnerability (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eBeyond genetic predisposition, environmental factors such as diet significantly influence late-onset AD risk. Both clinical and preclinical evidence strongly associate Western dietary patterns - characterized by high levels of saturated fats, refined sugars, and low nutrient content - with cognitive decline and increased AD susceptibility (reviewed in (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e). Notably, Western diet-induced pathologies such as neuroinflammation, glial activation, and A\u0026beta; accumulation overlap mechanistically with those linked to APOE-ɛ4 (\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e). However, the specific interactions between APOE-ɛ4 and Western diet in modulating synaptic transmission and plasticity in AD remain poorly understood.\u003c/p\u003e\n\u003cp\u003eWe hypothesized that the combination of genetic risk (APOE-ɛ4, APP, PS1) and acquired risk (Western diet, aging) factors would exacerbate synaptic pathology in an AD mouse model. To test this, we investigated hippocampal synaptic transmission and plasticity in APP/PS1 mice, with and without the APOE-ɛ4 allele, under control diet or Western diet conditions. Our findings demonstrate for the first time that the APOE-ɛ4 genotype amplifies, and a Western diet intake accelerates, hippocampal synaptic deficits in APP/PS1 mice through a synergistic interaction. Remarkably, these impairments were rescued by exogenous \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine supplementation, implicating disrupted \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine biosynthesis and impaired NMDAR-dependent plasticity as key mechanisms underlying this gene-environment interaction.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAnimals\u003c/h2\u003e\u003cp\u003eAPPswe/PS1dE9 (APP/PS1) mice, a widely used model of Alzheimer\u0026rsquo;s disease (AD) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), were obtained from The Jackson Laboratory (strain number 034832-JAX). APOE-ε4 KI, a mouse line pertinent to AD and atherosclerosis, with human APOE-ε4 sequences replacing those on the mouse \u003cem\u003eAPOE\u003c/em\u003e gene (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), was also obtained from The Jackson Laboratory (strain number 027894-JAX). These two lines were crossed to generate four genotypes: wild-type (wt), APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Mice of either sex were used in all experiments. All procedures were conducted in strict accordance with the European Union directive 2010/63/EU for animal care and use, and were approved by the French Ministry of Agriculture and Fisheries and the local ethical committee. Every effort was made to minimize animal suffering. Animal care was overseen by veterinarians and trained technicians specialized in rodent husbandry. Animals were housed under standard environmental conditions (12-h light-dark cycle, temperature: 22\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026deg;C and humidity: 50%) with ad libitum access to food and water. \u003cem\u003eEx vivo\u003c/em\u003e electrophysiological experiments were conducted at a fixed period during the light phase in a genotype experimenter\u003cem\u003e-\u003c/em\u003eblind approach.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDiet\u003c/h3\u003e\n\u003cp\u003eWild-type (wt), APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4 mice were housed in genotype-specific cages and provided ad libitum access to either a control diet or a Western diet. The control standard diet (A03, Safe, Augy, France) contained: 21% protein, 5% vegetable fat, 4% sucrose, and provided 3.4 kcal/g. The Western diet (TD.88137, Envigo Teklad, UK) was formulated to mimic human dietary patterns associated with metabolic dysfunction. It contained: 17% protein, 21% animal fat, 34% sucrose, 0.2% cholesterol, and provided 4.5 kcal/g. The diet was enriched in high-fructose corn syrup, saturated fats, and low fiber, with reduced micronutrient density and elevated milk protein. Dietary protocols were as follows: Mice in the control diet group received the standard diet continuously from birth until experimental evaluation. Mice in the Western diet group were maintained on the control diet until 5 months of age, after which the Western diet was introduced:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eFor animals evaluated at 7 months, the Western diet was administered for 2 months (from 5 to 7 months of age), based on prior evidence that short-term Western diet exposure increases oxidative stress and alters metabolic markers in APP/PS1 models (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eFor animals evaluated at 11 months, the Western diet was administered for 6 months (from 5 to 11 months of age), following studies showing that longer-term Western diet impairs cognition and promotes Aβ-related pathology in AD rodent models (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eBody weight was routinely monitored throughout the dietary intervention period to assess metabolic impact and ensure animal well-being.\u003c/p\u003e\n\u003ch3\u003eSlice preparation\u003c/h3\u003e\n\u003cp\u003eBrain hippocampal slices were obtained from 5, 7, 9 and 11 month-old wt, APP/PS1, APOE-ε4 and APP/PS1/APOE-ε4 mice, as described previously (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Animals were anesthetized with isoflurane and the brain rapidly removed and placed in ice-cold oxygenated artificial cerebrospinal fluid (aCSF) solution continuously gassed with carbogen (95% O\u003csub\u003e2\u003c/sub\u003e and 5% CO\u003csub\u003e2\u003c/sub\u003e) containing the following (in m\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eM\u003c/span\u003e): 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO\u003csub\u003e3\u003c/sub\u003e, 10 glucose, 1.3 MgCl\u003csub\u003e2\u003c/sub\u003e, 2 CaCl\u003csub\u003e2\u003c/sub\u003e, (pH\u0026thinsp;=\u0026thinsp;7.3\u0026ndash;7.4; 305\u0026ndash;310 mOsmol/kg). A block of tissue containing the hippocampus was extracted and sliced with a VT1200S vibratome (Leica VT1200S, Leica Biosystems, Nussloch, Germany). Acute transverse slices (350 \u0026micro;m thick) of the dorsal hippocampus were obtained by sectioning the brain at ~\u0026thinsp;45\u0026deg; from the coronal plane. The slices were transferred to a submersion recovery chamber with oxygenated aCSF at 33\u0026deg;C for 30 min and afterwards allowed to cool to room temperature and rest for 60 min minimum before experimentation. Following recovery period, hippocampal slices were transferred to a recording chamber installed on a \u003cem\u003eBX50\u003c/em\u003e fluorescence microscope (Olympus, Tokio, Japan), and held in place by a nylon mesh completely submerged and continuously perfused with gassed aCSF solution at a constant flow (3 mL/min) and temperature (32\u0026ndash;33\u0026deg;C).\u003c/p\u003e\n\u003ch3\u003eElectrophysiology\u003c/h3\u003e\n\u003cp\u003eBorosilicate glass (GC150F-7.5, Harvard Apparatus, Holliston, MA) capillaries, enclosing the recording microelectrodes, were pulled on a PP-83 vertical puller (Narishige, Tokyo, Japan) and the resulting pipettes filled with aCSF (series resistance 3\u0026ndash;5 MΩ). The CA3-CA1 hippocampal areas were identified with differential interference contrast light microscopy with a 4x Plan Achromat objective (Olympus).\u003c/p\u003e\u003cp\u003eField-excitatory postsynaptic potentials (fEPSPs) were evoked by orthodromic stimulation (100 ms duration) of afferent CA3 Schaffer collaterals using a concentric bipolar tungsten electrode (CBARC75, FHC, Bowdoin, USA) placed in the proximal CA1 region, \u0026gt;\u0026thinsp;200 \u0026micro;m away from the extracellular recording electrodes, located in the \u003cem\u003estratum radiatum\u003c/em\u003e of the distal CA1 area, close to the subiculum. To assess basal synaptic transmission efficiency, an input/output protocol was used where synaptic fEPSPs were evoked at a constant rate of 0.03 Hz stimulation of Schaffer collaterals (1 stimuli at 30 s intervals) using incremental 1V stimulation intensities (0-10V) and the resulting fEPSPs slope measured as a function of stimulus intensity. The fEPSPs slope was calculated as a linear fit of the rising phase, between time points set in the baseline period and corresponding to 20% and 60% of the peak amplitude. Data from three consecutive fEPSPs were collected for each stimulation intensity. To analyze pre-synaptic activity, we performed a paired-pulse protocol consisting in two consecutive stimuli separated by 50 ms, delivered every 30 s. The paired-pulse ratio (PPR) between the slopes of the two consecutive fEPSPs (fEPSP2/fEPSP1) was quantified.\u003c/p\u003e\u003cp\u003eLTP experiments were done as previously (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Briefly, fEPSPs were evoked at a constant rate of 0.03 Hz with the stimulus intensity set at 30\u0026ndash;40% of the maximum amplitude without triggering population spikes. After obtaining a stable baseline for at least 20 min (\u0026lt;\u0026thinsp;10% change), LTP was induced by applying a high frequency stimulation (HFS) protocol (100 Hz for 1 s, repeated three times at 20 s intervals). After LTP induction, fEPSPs were recorded for \u0026gt;\u0026thinsp;60 min. The change in the slope of the fEPSP was evaluated 50\u0026ndash;60 min post-HFS and normalized to the slope measured during the 10 min immediately before HFS. Post-tetanic potentiation (PTP) was assessed as the average fEPSPs slope obtained in the first 3 min after LTP induction.\u003c/p\u003e\u003cp\u003eElectrophysiological recordings of the NMDAR-component of fEPSPs (NMDAR-fEPSPs) were done as previously (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Briefly, the NMDAR contribution was extracted from global fEPSPs using picrotoxin (100 \u0026micro;M), NBQX (10 \u0026micro;M) and low external Mg\u003csup\u003e2+\u003c/sup\u003e concentration (0.2 mM) in the perfused aCSF, to block GABA receptors, AMPA/kainate receptors and remove the NMDAR Mg\u003csup\u003e2+\u003c/sup\u003e channel block, respectively. In some experiments, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine (50 \u0026micro;M) was directly applied in the perfused aCSF, immediately after the baseline period for NMDAR-fEPSPs and 20 min before recording input/output and LTP experiments, and then continuously present thorough the experiment.\u003c/p\u003e\u003cp\u003eData were acquired using a Multiclamp 700A amplifier (Molecular Devices, Sunnyvale, CA) controlled with pCLAMP 10 software (Molecular Devices) on current-clamp mode. Recordings were filtered at 2 kHz and digitized at 10 kHz using a Digidata 1322A digitizer interface (Axon Instruments, Inc.) and continuously stored on a personal computer. Data were collected and analyzed online and offline, respectively, using Clampfit from pCLAMP 10 software.\u003c/p\u003e\n\u003ch3\u003eMeasurement of Amino Acids in Hippocampal Extracellular medium\u003c/h3\u003e\n\u003cp\u003eFor the simultaneous measurement of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine and glycine, a laser-induced fluorescence capillary electrophoresis detection method was employed as previously (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Briefly, brain hippocampal transverse 350 \u0026micro;m slices obtained from 7-month-old wt, APP/PS1, APOE-ε4 and APP/PS1/APOE-ε4 mice were transferred to a submersion recovery chamber with oxygenated aCSF at 33\u0026deg;C for 45 min. Extracellular medium was quickly removed, frozen using liquid nitrogen and stored at -80\u0026deg;C.\u003c/p\u003e\u003cp\u003eExtracellular levels of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine and glycine were then determined. Briefly, pooled slices were deproteinized by addition of cold trichloroacetic acid (TCA) to a 4% final concentration. The suspension was centrifuged at 16,800 \u003cem\u003eg\u003c/em\u003e for 10 min to pellet the protein content used for protein quantification. TCA was then removed from the supernatant with water-saturated diethyl ether and stored at -80\u0026deg;C. Samples were analyzed with a commercial laser-induced fluorescence capillary electrophoresis (CE-LIF) (CE: Beckman Coulter (Brea, California, US), P/ACE MDQ; LIF: Picometrics (Lab\u0026egrave;ge, France)), LIF-UV-02, 410 nm 20 mW) as follows: samples were processed for micellar CE-LIF and were fluorescently derivatized at RT for 60 min with napthalene-2,3-dicarboxaldehyde (NDA) before being analyzed by CE using a hydroxypropyl-b-cyclodextrin (HP-b-CD) based chiral separation buffer. All electropherograms data were collected and analyzed using Karat 32 software v8.0 (Beckman Coulter, France). The amounts of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine and glycine were normalized to the protein content determined from pooled hippocampal slices by the Lowry method using the BCA protein Pierce assay (ThermoScientific, CA, USA) assay with bovine serum albumin (BSA) as a standard. The quantity of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine and glycine in the samples was determined from a standardized curve while peak identification was made according the retention time of reference standards and by spiking the fraction with the amino acid.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eDrugs and chemicals\u003c/h2\u003e\u003cp\u003eStock solutions were made and diluted with appropriate solvent before bath application. Drugs used were \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine, glycine (50 \u0026micro;M, Sigma-Aldrich, Merck, Germany), NMDA-R antagonist APV/AP-5 (10 \u0026micro;M, Tocris Bioscience, UK), AMPA and kainate receptors antagonist NBQX (10 \u0026micro;M, Tocris Bioscience), GABA\u003csub\u003eA\u003c/sub\u003eR selective antagonist picrotoxin (100 \u0026micro;M, Tocris Bioscience). Unless stated otherwise all remaining saline medium components and reagents were purchased from Sigma-Aldrich.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData collection and statistical analyses\u003c/h3\u003e\n\u003cp\u003eNo statistical method was used to predetermine sample size. Sample size was chosen based on prior experience for each experiment, to yield adequate power to detect specific effects. To avoid possible bias, data collection and analysis was performed blind.\u003c/p\u003e\u003cp\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM of the \u003cem\u003en\u003c/em\u003e number of independent experimental units (with N number of animals and n number of slices). All data were analyzed using GraphPad Prism software (Versions 5.0 and 8.0, GraphPad, USA). Data were first screened for a Gaussian distribution with Kolmogorov-Smirnov test: normal distributed data with one independent variable (e.g. genotype) was analyzed using one-way ANOVA followed by Dunnett\u0026rsquo;s or Tukey\u0026rsquo;s parametric post hoc tests for multiple-comparisons or two-tailed t-test for dual-comparisons; normal distributed data with two or more independent variables (e.g. genotype, voltage) was analyzed using two-way ANOVA followed by Bonferroni\u0026rsquo;s multiple-comparison parametric post hoc test; non-normal distributed data was analyzed by Dunn\u0026rsquo;s multiple-comparison non-parametric post hoc test. The significance level was set at a 95% confidence level with *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eHippocampal Basal Synaptic Transmission Is Impaired in APP/PS1/APOE-ɛ4 Mice\u003c/h2\u003e\n\u003cp\u003eThe cortico-hippocampal circuitry, particularly the glutamatergic synapses between CA3 and CA1 regions, plays a central role in hippocampal-dependent memory processing (\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e). Disruption or loss of these synapses contributes to explicit memory impairments, a hallmark early cognitive deficit in AD (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). To investigate whether basal synaptic transmission is influenced by the APOE-ɛ4 genotype in the context of AD, we crossed APPswe/PS1dE9 mice - a widely used model of familial (early-onset) AD (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e), with APOE-ɛ4 knock-in (APOE-ɛ4-ki) mice, which carry the most significant genetic risk factor for sporadic (late-onset) AD (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWe generated four mouse lines: wt, APP/PS1, APOE-ɛ4, and APP/PS1/APOE-ɛ4, and evaluated hippocampal basal synaptic transmission at 5, 7, 9, and 11 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea-d). Synaptic transmission at CA3-CA1 synapses was assessed using an input/output (I/O) protocol, measuring the slope of the field excitatory postsynaptic potentials (fEPSPs), which reflects excitatory transmission primarily mediated by AMPA and kainate receptors.\u003c/p\u003e\n\u003cp\u003eIn wt mice, input/output (I/O) relationships remained stable across ages, at 5 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea), 7 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb), 9 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec), and 11 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ed) - with the complete data summarized in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef. Across the evaluation period, APOE-\u0026epsilon;4 mice exhibited mild but non-significant reductions in synaptic transmission, while APP/PS1 mice showed transient significant deficits at 7 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec and \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef, 0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 vs wt 0.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 mV/ms at 10 V stimulation, n\u0026thinsp;=\u0026thinsp;17, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) that were not sustained at 9 or 11 months - findings consistent with previous reports on both APPswe/PS1dE9 and APOE-ɛ4-ki mice (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn contrast, APP/PS1/APOE-ɛ4 mice exhibited significant deficits in basal synaptic transmission beginning at 7 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec and \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef, 0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 vs wt 0.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 mV/ms at 10 V stimulation, n\u0026thinsp;=\u0026thinsp;17, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), which became more pronounced at 9 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ed and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef, 0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 vs wt 0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 mV/ms at 10 V stimulation, n\u0026thinsp;=\u0026thinsp;15, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and 11 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ee and \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef, 0.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 vs wt 0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10 mV/ms at 10 V stimulation, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). These synaptic impairments were unlikely to be caused by changes in presynaptic release probability, as the paired-pulse ratio remained stable across genotypes and ages, with values consistently above 1.5, indicating intact presynaptic function and a low basal release probability typical of CA3-CA1 synapses (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eg). Together, these results suggest that the synergistic interaction between the APP/PS1 and APOE-ɛ4 genotypes, but not either genotype alone, drives progressive basal synaptic transmission dysfunction from 7 months onward.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eAPOE-ɛ4 Genotype Exacerbates Hippocampal Synaptic Plasticity Deficits in APP/PS1 Mice\u003c/h2\u003e\n\u003cp\u003eEarly synaptic plasticity dysfunction is a hallmark of AD, with deficits in CA3-CA1 activity dependent long-term potentiation (LTP) observed in various AD models, including APP/PS1 mice (\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e). Although APOE-ɛ4 has also been linked with synaptic dysfunction (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), its specific impact on LTP deficits in AD models remains incompletely characterized.\u003c/p\u003e\n\u003cp\u003eTo address this, we recorded LTP in acute hippocampal slices from wild-type (wt), APP/PS1, APOE-ɛ4 knock-in, and APP/PS1/APOE-ɛ4 mice at 5, 7, 9, and 11 months of age. LTP was induced at CA3-CA1 synapses using a 100 Hz high-frequency stimulation (HFS) protocol applied three times to the Schaffer collaterals, and synaptic potentiation was considered when the fEPSPs slopes measured in between 50 to 60 minutes were increased (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003c/p\u003e\n\u003cp\u003eOur data indicate that both wt and APOE-ɛ4 mice exhibited stable LTP across all time points, in contrast to earlier studies reporting LTP deficits in APOE-ɛ4 knock-in models (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e). In APP/PS1 mice, however, significant LTP deficits emerged at 9 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ef, 140.58\u0026thinsp;\u0026plusmn;\u0026thinsp;4.00% vs wt 155.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.33%, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and became more pronounced at 11 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ed and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ef, 133.02\u0026thinsp;\u0026plusmn;\u0026thinsp;1.72% vs wt 152.97\u0026thinsp;\u0026plusmn;\u0026thinsp;2.36%, n\u0026thinsp;=\u0026thinsp;10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), consistent with previous reports in the APPswe/PS1dE9 AD model (\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e). Importantly, APP/PS1/APOE-ɛ4 mice exhibited a significantly greater reduction in LTP compared to APP/PS1 alone, as reflected by a marked reduction at 9 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ef, 128.39\u0026thinsp;\u0026plusmn;\u0026thinsp;2.00% vs wt 155.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.33%, n\u0026thinsp;=\u0026thinsp;18, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), which declined even further at 11 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ed and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ef, 120.41\u0026thinsp;\u0026plusmn;\u0026thinsp;4.30% vs wt 155.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.33%, n\u0026thinsp;=\u0026thinsp;8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\n\u003cp\u003eThese findings demonstrate that the APOE-ɛ4 genotype significantly exacerbates synaptic plasticity deficits in APP/PS1 mice, supporting a synergistic interaction between familial (APP/PS1) and sporadic (APOE-ɛ4) genetic risk factors in the progression of hippocampal synaptic dysfunction in late-onset AD.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eD-Serine Rescues Impaired NMDAR-Mediated Synaptic Plasticity in APP/PS1/APOE-ɛ4 Mice\u003c/h2\u003e\n\u003cp\u003eLTP depends on the activation of synaptic NMDA receptors (NMDARs), and disruptions in NMDAR function are thought to contribute to early synaptic deficits in AD. Previous studies have shown that A\u0026beta; and its derivatives directly reduce synaptic NMDAR activity, a phenomenon also observed in AD patients and animal models (\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e). Additionally, APOE-ɛ4 has been implicated in altered regulation of synaptic NMDAR regulation in AD (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTo investigate NMDAR dysfunction in our model, we recorded the NMDAR component of field excitatory postsynaptic potentials (NMDAR-fEPSPs) at CA3-CA1 synapses in 9-month-old mice, the time point when LTP deficits were first observed (see Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ed and f).\u003c/p\u003e\n\u003cp\u003eWild-type (wt) and APOE-ɛ4 mice showed comparable NMDAR-fEPSP I/O curves (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb). APP/PS1 mice exhibited a modest but non-significant reduction, whereas APP/PS1/APOE-ɛ4 mice displayed a significant decrease in NMDAR-fEPSP slopes (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb, 0.037\u0026thinsp;\u0026plusmn;\u0026thinsp;0.004 vs wt 0.080\u0026thinsp;\u0026plusmn;\u0026thinsp;0.015 mV/ms at 20 V stimulation, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05;), indicating greater NMDAR dysfunction due to the APOE-ɛ4 genotype.\u003c/p\u003e\n\u003cp\u003eBecause \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine - the endogenous co-agonist of synaptic NMDARs - is essential for NMDAR-dependent LTP and memory, and is known to be reduced in 3xTg-AD mice (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e), we next evaluated the co-agonist binding site occupancy of synaptic NMDARs. Following 30 minutes of baseline NMDAR-fEPSP recordings, bath application of \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine (50 \u0026micro;M) induced moderate and comparable increases in NMDAR-fEPSPs in both wt (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, 137.85\u0026thinsp;\u0026plusmn;\u0026thinsp;12.86% of baseline, n\u0026thinsp;=\u0026thinsp;8) and APOE-ɛ4 mice (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, 135.12\u0026thinsp;\u0026plusmn;\u0026thinsp;14.71% of baseline, n\u0026thinsp;=\u0026thinsp;8). These results are consistent with previous findings suggesting that NMDAR co-agonist sites at CA3-CA1 synapses are not fully saturated under basal conditions, particularly in AD models (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e). In APP/PS1 mice, \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine application resulted in a more pronounced increase in NMDAR-fEPSPs (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, 163.83\u0026thinsp;\u0026plusmn;\u0026thinsp;11.78% of baseline, n\u0026thinsp;=\u0026thinsp;9), and this effect was significantly greater in APP/PS1/APOE-ɛ4 mice (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, 179.23\u0026thinsp;\u0026plusmn;\u0026thinsp;9.90%, n\u0026thinsp;=\u0026thinsp;10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 vs wt), indicating a lower baseline occupancy of NMDAR co-agonist sites. These findings are consistent with the reduced NMDAR activity observed in APP/PS1/APOE-ɛ4 mice (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb) and suggest a deficiency in synaptic \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine availability.\u003c/p\u003e\n\u003cp\u003eWe hypothesized that such \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine deficits contribute to the LTP impairments seen in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ed). In support of this, LTP impairments in APP/PS1 and APP/PS1/APOE-ɛ4 mice were significantly rescued when exogenous \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine (50 \u0026micro;M) was applied in the perfused aCSF (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ed, e). \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine enhanced LTP across all genotypes but had a particularly strong recovery effect in APP/PS1 mice (control: 140.58\u0026thinsp;\u0026plusmn;\u0026thinsp;4.00% vs \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine: 161.34\u0026thinsp;\u0026plusmn;\u0026thinsp;8.87%, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and even more so in APP/PS1/APOE-ɛ4 mice (control: 128.39\u0026thinsp;\u0026plusmn;\u0026thinsp;2.00% vs \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine: 158.93\u0026thinsp;\u0026plusmn;\u0026thinsp;5.94%, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ee). These results point to reduced \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine availability as a key mechanism underlying NMDAR hypofunction and impaired synaptic plasticity in APP/PS1/APOE-ɛ4 mice.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eWestern diet Accelerates Synaptic Plasticity Deficits in APOE-ɛ4-carrier Mice\u003c/h2\u003e\n\u003cp\u003eIn addition to the well-established genetic risk conferred by the APOE-ɛ4 allele, lifestyle factors-particularly dietary habits-can significantly exacerbate susceptibility to late-onset AD (\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e). While high-fat diets have previously been associated with hippocampal synaptic plasticity impairments (\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e), the impact of the more complex Western diet - characterized by high levels of saturated fats, refined sugars, synthetic additives, and reduced protein content - on hippocampal synaptic function, especially in the presence of the APOE-ɛ4 genotype, remains poorly understood.\u003c/p\u003e\n\u003cp\u003eTo investigate this interaction, we exposed wt, APP/PS1, APOE-ɛ4, and APP/PS1/APOE-ɛ4 mice to either a standard control diet or a custom-formulated Western diet. We then assessed basal synaptic transmission and LTP in hippocampal slices (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea). The Western diet was introduced at 5 months of age and maintained for 2 months, a time window previously shown to induce neuropathological alterations in AD mouse models (\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e). The 7-month time point was selected as it precedes the typical onset of synaptic plasticity deficits in this model (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec, d) (\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eInterestingly, basal synaptic transmission was elevated across all genotypes on Western diet exposure compared to their respective control-diet counterparts (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb, c). At 7 months of age, significant increases in basal transmission were observed in wt (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), APP/PS1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), APOE-ɛ4 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and APP/PS1/APOE-ɛ4 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) mice on the Western diet. Despite this general enhancement, APP/PS1/APOE-ɛ4 mice still displayed impaired basal synaptic transmission relative to wt mice on the same diet (0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 vs. 1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 mV/ms, n\u0026thinsp;=\u0026thinsp;11, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb, c). Moreover, APOE-ɛ4 mice fed a Western diet also exhibited synaptic deficits compared to wt mice on the same diet (0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 vs. 1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 mV/ms, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), a phenotype not observed under control diet conditions. These findings suggest that while Western diet intake broadly increases basal synaptic activity across genotypes, it does not normalize or reverse synaptic vulnerability in APOE-ɛ4 genotype carriers.\u003c/p\u003e\n\u003cp\u003eInterestingly, the Western diet induced synaptic plasticity deficits at an earlier time point. At 7 months of age, while LTP remained intact under control diet conditions (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ee), significant impairments were observed in APOE-ɛ4 (131.83\u0026thinsp;\u0026plusmn;\u0026thinsp;7.13% vs. wt 158.42\u0026thinsp;\u0026plusmn;\u0026thinsp;4.31%, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and APP/PS1/APOE-ɛ4 mice (128.70\u0026thinsp;\u0026plusmn;\u0026thinsp;5.00% vs. wt 158.42\u0026thinsp;\u0026plusmn;\u0026thinsp;4.31%, n\u0026thinsp;=\u0026thinsp;16, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) following Western diet intake (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ed, e). Similar deficits were also observed at 11 months of age (data not shown), suggesting that these impairments persist beyond the early onset phase. Thus, just two months of Western diet exposure were sufficient to advance the onset of LTP deficits in APP/PS1/APOE-ɛ4 mice from 9 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ed, f) to 7 months (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ed, e), and to unmask previously absent impairments in APOE-ɛ4 mice. Notably, LTP in wt and APP/PS1 mice remained unaffected by the Western diet. These findings suggest that the Western diet selectively interacts with the APOE-ɛ4 genotype to advance and precipitate hippocampal synaptic plasticity deficits.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003e\u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-Serine Restores NMDAR-Dependent Synaptic Plasticity From Deficits Present in APOE-ɛ4-carrier Mice on a Western Diet\u003c/h2\u003e\n\u003cp\u003eGiven that \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine effectively rescued NMDAR-dependent synaptic plasticity deficits in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice under control diet conditions (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), we next investigated whether a similar \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine deficiency was involved in the LTP impairments observed at 7 months in mice fed a Western diet (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). To this end, we assessed synaptic NMDAR activity by recording the NMDAR component of field EPSPs (NMDAR-fEPSPs) using an I/O protocol in hippocampal slices from 7-month-old mice maintained on either control or Western diet (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eb, c).\u003c/p\u003e\n\u003cp\u003eUnder control diet conditions, all genotypes exhibited comparable NMDAR-fEPSP I/O curves (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eb). In contrast, Western diet (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ea-c) led to a significant reduction in NMDAR-mediated synaptic responses in APP/PS1 (0.006\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 mV/ms, n\u0026thinsp;=\u0026thinsp;10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), APOE-ɛ4 (0.055\u0026thinsp;\u0026plusmn;\u0026thinsp;0.004 mV/ms, n\u0026thinsp;=\u0026thinsp;14, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and APP/PS1/APOE-ɛ4 mice (0.047\u0026thinsp;\u0026plusmn;\u0026thinsp;0.004 mV/ms, n\u0026thinsp;=\u0026thinsp;11, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), relative to wt mice on the same diet (0.077\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 mV/ms, n\u0026thinsp;=\u0026thinsp;10). This contrasts with the increased basal synaptic transmission observed under Western diet in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb, suggesting that the previous general fEPSP enhancement is not mediated by NMDARs, but likely reflects increased AMPAR or kainate-driven excitability. These findings suggest that APOE-ɛ4 genotype carriers are particularly vulnerable to NMDAR hypofunction under Western diet conditions.\u003c/p\u003e\n\u003cp\u003eTo assess whether reduced \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine availability contributes to the observed NMDAR hypofunction, we evaluated co-agonist site occupancy at synaptic NMDARs by applying exogenous \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine (50 \u0026micro;M) to hippocampal slices from 7-month-old mice under either control or Western diet conditions (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ed, e). Under control diet conditions, all genotypes responded similarly to \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine application after 30 min, indicating comparable baseline co-agonist site occupancy. However, under Western diet exposure, \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine elicited significantly greater increases in NMDAR-fEPSPs in APOE-ɛ4 (173.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0%, n\u0026thinsp;=\u0026thinsp;13, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and APP/PS1/APOE-ɛ4 mice (182.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0%, n\u0026thinsp;=\u0026thinsp;10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) relative to wt controls (143.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0%, n\u0026thinsp;=\u0026thinsp;15). These findings suggest that Western diet reduces endogenous \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine availability in APOE-ɛ4 carriers, thereby limiting NMDAR activation and contributing to synaptic dysfunction.\u003c/p\u003e\n\u003cp\u003eTo confirm whether reduced NMDAR function was associated with altered co-agonist availability, we quantified extracellular levels of \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine, \u003cspan class=\"SmallCaps\"\u003el\u003c/span\u003e-serine (its biosynthetic precursor), and glycine from hippocampal slice perfusates using capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) (Fig.\u0026nbsp;6a). This method enables precise, simultaneous quantification of amino acids in small volume samples, providing insights into receptor ligand dynamics (\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e). Under control diet conditions, extracellular concentrations of \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine, \u003cspan class=\"SmallCaps\"\u003el\u003c/span\u003e-serine, and glycine did not differ significantly across genotypes, indicating preserved amino acid homeostasis in the hippocampus (Fig.\u0026nbsp;6b, d, f). In contrast, Western diet exposure led to a marked reduction in \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine and \u003cspan class=\"SmallCaps\"\u003el\u003c/span\u003e-serine extracellular levels specifically in APP/PS1/APOE-ɛ4 mice, while glycine remained unaffected. \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine levels in these mice dropped significantly compared to their control diet counterparts (0.057\u0026thinsp;\u0026plusmn;\u0026thinsp;0.003 nmol/mg vs. 0.076\u0026thinsp;\u0026plusmn;\u0026thinsp;0.005 nmol/mg, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fig.\u0026nbsp;6c), as did levels of its biosynthetic precursor \u003cspan class=\"SmallCaps\"\u003el\u003c/span\u003e-serine (1.602\u0026thinsp;\u0026plusmn;\u0026thinsp;0.086 nmol/mg vs. 2.140\u0026thinsp;\u0026plusmn;\u0026thinsp;0.167 nmol/mg, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fig.\u0026nbsp;6e). In contrast, glycine concentrations remained stable across all genotypes and dietary conditions (Fig.\u0026nbsp;6g), suggesting that the observed NMDAR co-agonist deficiency is specific to the \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine pathway. These results further support that Western diet selectively impairs \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine metabolism in APP/PS1/APOE-ɛ4 mice, contributing to reduced NMDAR activation and synaptic dysfunction.\u003c/p\u003e\n\u003cp\u003eGiven the observed reductions in \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine levels and \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine-dependent NMDAR activity, we next tested whether exogenous \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e) could restore the impaired synaptic function observed in 7-month-old APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice fed with a Western diet (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Interestingly, \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine application (50 \u0026micro;M) effectively rescued LTP impairments in both APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice fed a Western diet (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eb). In APOE-ɛ4 mice, LTP was significantly improved following \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine treatment (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003ec, Western diet: 131.83\u0026thinsp;\u0026plusmn;\u0026thinsp;7.13% vs. Western diet\u0026thinsp;+\u0026thinsp;\u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine: 160.46\u0026thinsp;\u0026plusmn;\u0026thinsp;6.30%, n\u0026thinsp;=\u0026thinsp;9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05;), and a similar rescue was observed in APP/PS1/APOE-ɛ4 mice (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003ec, Western diet: 128.70\u0026thinsp;\u0026plusmn;\u0026thinsp;5.00% vs. Western diet\u0026thinsp;+\u0026thinsp;\u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine: 155.91\u0026thinsp;\u0026plusmn;\u0026thinsp;4.08%, n\u0026thinsp;=\u0026thinsp;10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003eOur results show that exogenous \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine not only rescued LTP deficits in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice under control diet conditions (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), but also mitigated the synaptic plasticity impairments induced by Western diet in 7-month-old APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e). These effects support a role for reduced \u003cspan class=\"SmallCaps\"\u003ed\u003c/span\u003e-serine availability in the synaptic deficits observed across genotypes and diet conditions, particularly in the presence of APOE-ɛ4 and Western diet.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSynaptic dysfunction is recognized as a central and early feature of AD, often preceding overt amyloid plaque deposition, tau pathology, or neuronal loss (\u003cspan additionalcitationids=\"CR60\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e). Reductions in hippocampal synaptic density, alterations in dendritic spine morphology, and impairments in synaptic plasticity, particularly long-term potentiation (LTP), are tightly linked to cognitive decline (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e). Although transgenic mouse models have provided invaluable insights into these processes, they fall short of recapitulating the complexity of sporadic, late-onset AD, which accounts for more than 95% of AD cases (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Notably, few models integrate both genetic and modifiable lifestyle risk factors - such as the APOE-ε4 allele and Western dietary patterns - that better reflect real-world vulnerability. To address this, we combined APOE-ε4 expression and Western diet exposure in APP/PS1 mice, providing a model that may more closely reflect the pathophysiological conditions underlying early synaptic dysfunction.\u003c/p\u003e\u003cp\u003eAlthough APOE-ε4 is the strongest genetic risk factor for late-onset AD, its effects on synaptic function remain incompletely understood (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). APOE-ε4 knock-in mice show increased Aβ burden, impaired amyloidal clearance, and heightened neuroinflammation (\u003cspan additionalcitationids=\"CR64\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e). Even without amyloid pathology, APOE-ε4 mice exhibit early, sex-dependent cognitive and behavioral changes (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan additionalcitationids=\"CR67\" citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e), accompanied by reduced synaptic markers and spine density (\u003cspan additionalcitationids=\"CR70\" citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e). However, studies of synaptic physiology in APOE-ε4 models have been inconsistent, with some reporting impaired synaptic transmission (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e) and LTP (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), while others found no deficits or even enhancements (\u003cspan additionalcitationids=\"CR75\" citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e), possibly reflecting different experimental conditions, mice strains or age. In our study, APOE-ε4 mice under control diet showed no synaptic impairment, consistent with previous reports (\u003cspan additionalcitationids=\"CR75\" citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e). However, the combination of APOE-ε4 and APP/PS1 mutations led to progressive deficits in synaptic transmission and LTP, with impairments in synaptic transmission emerging at 7 months and LTP deficits appearing by 9 months under control diet conditions, suggesting that APOE-ε4 aggravates synaptic vulnerability in the context of amyloid pathology (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These findings highlight a synergistic interaction between APOE-ε4 and amyloidogenic pathology in the early synaptic pathogenesis of AD. Our data further reveal that the impaired synaptic plasticity observed in APP/PS1/APOE-ɛ4 mice is strongly associated with NMDAR hypofunction, likely derived from reduced availability of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine, the essential co-agonist at synaptic NMDARs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These findings align with our previous work showing that \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine supplementation restores LTP and memory in 3xTg-AD mice (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and supports synaptic NMDAR function in other AD models (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Notably, exogenous \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine rescued both NMDAR-mediated responses and LTP deficits in APP/PS1 and APP/PS1/APOE-ɛ4 mice, underscoring the therapeutic potential of targeting \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine signaling in early AD-related synaptic pathology.\u003c/p\u003e\u003cp\u003eWhile high-fat diets have been shown to disrupt synaptic plasticity and cognitive performance (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e), far less is known about the effects of a full Western diet, which more closely mimics modern dietary patterns and real-world risk by combining high levels of saturated fat, refined sugars, synthetic additives, and reduced protein. Epidemiological studies have increasingly linked Western diet consumption to an elevated risk of AD (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e). While its long-term metabolic consequences - such as obesity, insulin resistance, and cardiovascular disease - are well documented (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e), the specific mechanisms through which Western diet impacts brain function, particularly in the early stages of AD and in interaction with the APOE-ε4 genotype, remain poorly defined. In the brain, Western diet has been associated with increased Aβ accumulation, glial activation, blood-brain barrier dysfunction and neuroinflammation (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). However, its direct influence on synaptic physiology, especially under APOE-ε4-related vulnerability, is still largely unexplored.\u003c/p\u003e\u003cp\u003eWe found that just two months of Western diet intake is sufficient to precipitate significant hippocampal synaptic plasticity deficits in APOE-ε4 and APP/PS1/APOE-ε4 mice - deficits not observed under control diet conditions at this age (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This early onset of LTP impairment, alongside the induction of synaptic deficits in APOE-ε4 carriers, supports a synergistic interaction between diet and genotype, as previously suggested (\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e). Importantly, this occurred without affecting LTP in WT or APP/PS1 mice, highlighting a selective vulnerability of APOE-ε4 carriers.\u003c/p\u003e\u003cp\u003eIn regards to basal synaptic transmission, Western diet increased fEPSPs across all genotypes; however, APOE-ε4 carriers continued to show weaker transmission compared to wt and APP/PS1 mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), indicating that Western diet does not normalize intrinsic genotype-dependent basal transmission vulnerability. While high-fat diets have been linked to hippocampal baseline neurotransmission impairments (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e, \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e), Western diet intake, consistent with our findings, has conversely been associated with increased basal neuronal excitability in various brain regions (\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e). This supports a complex, multifaceted impact of Western diet on hippocampal function - particularly in APOE-ɛ4 carriers - distinct from the effects observed with more simplified high-fat diets. Notably, despite the general enhancement in fEPSPs slopes, NMDAR-mediated responses were significantly reduced in APOE-ε4, APP/PS1, and APP/PS1/APOE-ε4 mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), suggesting that the increased basal synaptic transmission under Western diet is likely driven by AMPAR or kainate-driven excitability, not NMDARs. This selective NMDAR hypofunction, particularly in APOE-ε4 carriers, may underlie the failure to sustain synaptic plasticity. To our knowledge, this is the first evidence that Western diet alone is sufficient to induce synaptic plasticity dysfunction in APOE-ε4 carriers, where such deficits were absent under control diet conditions, and advances their onset in APP/PS1/APOE-ε4 mice.\u003c/p\u003e\u003cp\u003eOur data further reveal that the synaptic vulnerability observed in APOE-ε4 carriers under Western diet conditions is tightly linked to reduced availability of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). While synaptic NMDAR responses remained intact under control diet across all genotypes, Western diet exposure significantly reduced NMDAR-mediated transmission in APOE-ε4 and APP/PS1/APOE-ε4 mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), supporting the view that these genotypes are especially susceptible to diet-induced glutamatergic disruption (\u003cspan additionalcitationids=\"CR84\" citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e). Importantly, this NMDAR hypofunction was associated with a greater potentiation of NMDAR-fEPSPs following exogenous \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine application, suggesting a deficit in endogenous co-agonist availability. Supporting this, CE-LIF biochemical analysis confirmed significantly reduced extracellular \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine and its biosynthetic precursor \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine in the hippocampus of Western diet-fed APP/PS1/APOE-ε4 mice, while glycine levels remained unchanged (\u003cb\u003eFig.\u0026nbsp;6\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eWhile \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine has been consistently shown to support cognitive function in aging-related decline (\u003cspan additionalcitationids=\"CR87\" citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e), its role in AD remains more controversial. Across various AD models and patient cohorts, some studies have reported reduced \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine levels and beneficial effects following supplementation (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR90 CR91\" citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e). In contrast, others have found elevated \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine levels linked to excitotoxicity and disease progression (\u003cspan additionalcitationids=\"CR94 CR95 CR96\" citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e), while a few report no significant changes at all (\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e, \u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e). These discrepancies likely reflect differences in AD mouse models, their underlying glycolytic and metabolic states, or the disease stage in patient samples. In general, \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine appears beneficial in prodromal and early-phase AD - approximately 4\u0026ndash;8 months in APP/PS1 mice - but may exert deleterious effects in intermediate and late disease stages (\u003cspan additionalcitationids=\"CR87\" citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e, \u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e). Here, we showed that \u003csub\u003eD\u003c/sub\u003e-serine supplementation fully rescued LTP deficits at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e), and also restored function in older animals (9\u0026ndash;11 months) under control diet (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This suggests that in the APP/PS1/APOE4 model, NMDAR hypofunction persists beyond early stages, potentially extending the therapeutic window for \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine or \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine intervention. These results align with our previous findings that both \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e- and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine levels are reduced in AD patients and in 6\u0026ndash;7-month-old 3xTg-AD mice, and that \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e- and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine supplementation can restore synaptic plasticity and memory function in the 3xTg-AD model (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). This reduction in \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine was linked to altered astrocytic glycolytic flux and disruption of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine biosynthesis, observed in both human and animal models (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR101\" class=\"CitationRef\"\u003e101\u003c/span\u003e, \u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e- and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine reductions observed in APP/PS1/APOE-ε4 mice likely reflect a shift in astrocytic metabolism toward aerobic glycolysis, a pattern independently induced by both APOE-ε4 expression and Western diet (\u003cspan citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e). Notably, rodents exposed to high-fat and Western diets (\u003cspan additionalcitationids=\"CR105 CR106 CR107\" citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e), as well as APOE4-expressing astrocytes (\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e, \u003cspan additionalcitationids=\"CR110\" citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e), exhibit similarly reprogrammed metabolic profiles - marked by decreased oxidative metabolism and reduced biosynthetic capacity - suggesting a shared vulnerability that may converge on serine metabolism. These combined stressors likely divert glycolytic flux away from the phosphorylated pathway of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine synthesis (\u003cspan citationid=\"CR102\" class=\"CitationRef\"\u003e102\u003c/span\u003e, \u003cspan citationid=\"CR104\" class=\"CitationRef\"\u003e104\u003c/span\u003e), thereby diminishing NMDAR co-agonist availability and compromising astrocyte-neuron metabolic coupling (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e, \u003cspan citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eInterestingly, while \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine has therapeutic potential, its clinical use is limited by nephrotoxicity concerns, particularly in rodents (\u003cspan citationid=\"CR114\" class=\"CitationRef\"\u003e114\u003c/span\u003e). \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine, by contrast, shares neuroprotective effects in AD and aging - supporting protein homeostasis, anti-inflammatory responses, and synaptic resilience - with a more favorable safety profile (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR115\" class=\"CitationRef\"\u003e115\u003c/span\u003e). Thus, targeting astrocytic \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine biosynthesis may offer a safer route for therapeutic intervention in APOE-ε4 carriers.\u003c/p\u003e\u003cp\u003eTogether, these results highlight the convergence of genetic (APOE-ε4) and environmental (Western diet) risk factors on \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine/NMDAR signaling as a key mechanistic pathway in early synaptic dysfunction in AD, and a potential target for therapeutic strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study provides new mechanistic insight into how the APOE-ε4 genotype and Western diet synergistically aggravate and accelerate hippocampal synaptic dysfunction through disruption of \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine/NMDAR signaling. These findings underscore the necessity of considering both genetic and lifestyle risk factors in modeling and understanding early late-onset AD pathophysiology. Furthermore, they highlight astrocytic serine biosynthesis as a metabolically sensitive and modifiable pathway with therapeutic relevance. Targeting \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e- and \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine metabolism may offer a safer and effective early intervention approach, especially for individuals carrying the APOE-ε4 allele.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAlzheimer\u0026rsquo;s disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPOE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eApolipoprotein E\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPOE-ɛ4\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eApolipoprotein E ɛ4 allele\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPP/PS1\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmyloid precursor protein-Presenilin-1\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAβ\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmyloid-beta\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCE-LIF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCapillary electrophoresis with laser-induced fluorescence\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCentral nervous system\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-ser\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003ed\u003c/span\u003e-serine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-ser\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003el\u003c/span\u003e-serine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003efEPSP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eField excitatory postsynaptic potential\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHigh-frequency stimulation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eI/O\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInput-output\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eKI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eKnock-in\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLTP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLong-term potentiation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNMDAR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eN-methyl-D-aspartate receptor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNMDAR-fEPSP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNMDAR-mediated field excitatory postsynaptic potential\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePPF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePaired-pulse facilitation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSchaffer collaterals\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWestern diet\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ewt\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWild-type.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis study was funded by INSERM (to P.A., O.S.H.R.); CNRS (to P.A., O.S.H.R.); the Agence Nationale de la Recherche/ EU Joint Programme - Neurodegenerative Disease Research (JPND) (JPND DACAPO-AD: RPB16004GGA) and Vaincre Alzheimer (RAK20002GGA; to O.S.H.R., M.M. and O.A.). This work benefited from the support of various facilities granted by INSERM and LabEX BRAIN ANR-10-LABX-43.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.M. performed the experiments, analyzed the data, and drafted the manuscript. O.A., M.I., and L.B.A. assisted with CE-LIF experiments and their analysis. C.P. assisted with additional experiments. H.E. was responsible for mouse breeding and genotyping, and L.D. oversaw animal care. O.S.H.R. and P.A. supervised the project, contributed to data interpretation, and provided manuscript review and editing. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors gratefully acknowledge the staff of the Neurocentre Magendie Animal Facility and the PUMA (Magendie Unified Platforms) for their dedicated support in animal care and experimental logistics. We also thank the technical team in Oliet\u0026rsquo;s lab for their valuable assistance throughout the project. We are particularly grateful to all past and present members of the Oliet lab for their insightful discussions and continuous support. Finally, we thank the entire JPND DACAPO-AD consortium for all the fruitful and stimulating scientific exchanges.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eQuerfurth HW, Laferla FM. Alzheimer\u0026rsquo;s Disease. N Engl J Med. 2010;362:329\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSelkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer\u0026rsquo;s disease at 25 years. EMBO Mol Med. 2016;8(6):1\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSelkoe DJ. Alzheimer\u0026rsquo;s disease is a synaptic failure. Sci (80-). 2002;298(5594):789\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArendt T. 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Neurosci Lett. 2023;792:136958.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin CH, Yang HT, Lane HY, D-glutamate. D-serine, and D-alanine differ in their roles in cognitive decline in patients with Alzheimer\u0026rsquo;s disease or mild cognitive impairment. Pharmacol Biochem Behav. 2019;185(2):172760.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBalu DT, Pantazopoulos H, Huang CCY, Muszynski K, Harvey TL, Uno Y, et al. Neurotoxic astrocytes express the D-serine synthesizing enzyme, serine racemase, in Alzheimer\u0026rsquo;s disease. Neurobiol Dis. 2019;130(June):104511.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen X, Calandrelli R, Girardini J, Yan Z, Tan Z, Xu X, Hiniker AZS. PHGDH expression increases with progression of Alzheimer\u0026rsquo;s disease pathology and symptoms. Cell Metab. 2022;34(5):651\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMadeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brand\u0026atilde;o CO, Reis T et al. D-serine levels in Alzheimer\u0026rsquo;s disease: Implications for novel biomarker development. Transl Psychiatry. 2015;5(February).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBiemans EALM, Verhoeven-Duif NM, Gerrits J, Claassen JAHR, Kuiperij HB, Verbeek MM. CSF d-serine concentrations are similar in Alzheimer\u0026rsquo;s disease, other dementias, and elderly controls. Neurobiol Aging. 2016;42:213\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNagata Y, Borghi M, Fisher GH, D\u0026rsquo;Aniello A. Free d-serine concentration in normal and Alzheimer human brain. Brain Res Bull. 1995;38(2):181\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T, De Strooper B, et al. 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Neural Regen Res. 2024;20(82271214):2264\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChristensen A, Pike CJ. Effects of APOE Genotype and Western Diet on Metabolic Phenotypes in Female Mice. Metabolites. 2023;13(2).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin L, Basu R, Chatterjee D, Templin AT, Flak JN, Johnson TS. Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet. Sci Rep. 2023;13(1):1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePopov A, Brazhe N, Fedotova A, Tiaglik A, Bychkov M, Morozova K, et al. A high-fat diet changes astrocytic metabolism to promote synaptic plasticity and behavior. Acta Physiol. 2022;236(1):1\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu CW, Hung CY, Hirase H, Tain YL, Lee WC, Chan JYH, et al. 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APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020;581(7806):71\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu L, Zhang X, Zhao L. Human apoe isoforms differentially modulate brain glucose and ketone body metabolism: Implications for Alzheimer\u0026rsquo;s disease risk reduction and early intervention. J Neurosci. 2018;38(30):6665\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQi G, Mi Y, Shi X, Gu H, Brinton RD, Yin F. ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism. Cell Rep. 2021;34(1):108572.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFern\u0026aacute;ndez-Moncada I, Lavanco G, Fundazuri UB, Bollmohr N, Mountadem S, Dalla Tor T et al. A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice. Nat Commun. 2024;15(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeftah A, Hasegawa H, Kantrowitz JT. D-Serine: A Cross Species Review of Safety. Front Psychiatry. 2021;12(August):1\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePhone Myint SMM, Sun LY. L-serine: Neurological Implications and Therapeutic Potential. Biomedicines. 2023;11(8).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"alzheimers-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"azrt","sideBox":"Learn more about [Alzheimer's Research and Therapy](http://alzres.biomedcentral.com/)","snPcode":"13195","submissionUrl":"https://submission.nature.com/new-submission/13195/3","title":"Alzheimer's Research \u0026 Therapy","twitterHandle":"@AlzheimersRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease, APOE-ε4, Western diet, NMDAR, d-serine, hippocampus, synaptic plasticity, APP/PS1 mice, gene-environment interaction.","lastPublishedDoi":"10.21203/rs.3.rs-7320776/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7320776/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlzheimer’s disease (AD) is a progressive neurodegenerative disorder thought to result from complex interactions between genetic and environmental risk factors. The APOE-ε4 allele is the strongest genetic contributor to late-onset AD, while a Western diet - high in saturated fats and refined sugars - is a major lifestyle-related risk factor associated with AD progression. However, how these two factors interact at an early stage of the disease remains unclear. In this study, we examined their combined impact on hippocampal synaptic transmission and plasticity in an AD mouse model and evaluated whether supplementation with d-serine, the key NMDAR co-agonist, could reverse the resulting deficits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the combined effects of genetic and dietary risk factors on synaptic function, we crossed APP/PS1 mice with APOE-ε4 KI mice andgenerated four mouse lines: wild-type, APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Hippocampal synaptic transmission and plasticity, NMDAR function and d- and l-serine levels were evaluated using a combination of electrophysiological recordings, pharmacological interventions and capillary electrophoresis in brain slices, under either control or Western diet conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA significant impairment of both basal excitatory synaptic transmission and long-term potentiation (LTP) was detected in APP/PS1 mice by 9 months of age. These deficits were significantly more pronounced in APP/PS1/APOE-ε4 mice. Notably, Western diet accelerated these impairments, with significant deficits already present at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice. Mechanistically, these impairments were associated with reduced d-serine availability and NMDAR hypofunction at CA3-CA1 synapses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study provides the first direct evidence of a specific and synergistic interaction between the APOE-ε4 genotype and Western diet in advancing and exacerbating hippocampal synaptic dysfunction in an AD mouse model. These findings highlight d-serine/NMDAR signaling as a key mechanistic pathway through which genetic and environmental risk factors converge in early AD, and underscore the potential of targeting astrocytic d-serine biosynthetic pathways as a promising therapeutic strategy for APOE-ε4 carriers at risk for late-onset AD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e","manuscriptTitle":"APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 18:33:15","doi":"10.21203/rs.3.rs-7320776/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-07T11:24:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-22T21:49:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T16:13:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"143591421500983993600465315743354879849","date":"2025-11-11T06:47:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65373914409709596476507288799793109130","date":"2025-11-09T17:53:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"259467737482888846715466712453446174413","date":"2025-11-09T14:54:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-29T14:38:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"83594480922398137622910868223248043666","date":"2025-09-18T09:17:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"241829642595413219395893510499700381960","date":"2025-09-15T18:50:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"229896727395501982487995885813221851952","date":"2025-08-31T06:36:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-19T08:09:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-08T06:40:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-08T06:40:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Alzheimer's Research \u0026 Therapy","date":"2025-08-07T16:30:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"alzheimers-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"azrt","sideBox":"Learn more about [Alzheimer's Research and Therapy](http://alzres.biomedcentral.com/)","snPcode":"13195","submissionUrl":"https://submission.nature.com/new-submission/13195/3","title":"Alzheimer's Research \u0026 Therapy","twitterHandle":"@AlzheimersRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"955d2d05-753b-453a-a989-f113cec12cd9","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:13:39+00:00","versionOfRecord":{"articleIdentity":"rs-7320776","link":"https://doi.org/10.1186/s13195-026-01992-y","journal":{"identity":"alzheimers-research-and-therapy","isVorOnly":false,"title":"Alzheimer's Research \u0026 Therapy"},"publishedOn":"2026-02-25 15:59:06","publishedOnDateReadable":"February 25th, 2026"},"versionCreatedAt":"2025-08-27 18:33:15","video":"","vorDoi":"10.1186/s13195-026-01992-y","vorDoiUrl":"https://doi.org/10.1186/s13195-026-01992-y","workflowStages":[]},"version":"v1","identity":"rs-7320776","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7320776","identity":"rs-7320776","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}