ABCA7 deficiency exacerbates glutamate excitotoxicity in Alzheimer’s disease mice – a new pharmacological target for Glu-related neurotoxicity

Abstract Increasing attention has been directed towards the perturbation of glutamate (Glu) and γ-aminobutyric acid (GABA) homeostasis during the pathogenesis of Alzheimer’s disease (AD). The prevailing disequilibrium, stemming from hyperactivation of the glutamatergic system, culminates in progressive neuronal impairment and cognitive deterioration. This study aimed to elucidate the contributory role of the ATP-binding cassette transporter A7 (ABCA7), identified as the second most critical genetic determinant in AD, in glutamatergic-associated neurotoxicity. This endeavor sought to advance molecular comprehension of neurological disorders where Glu-GABA neurotransmission represents a pivotal pharmacotherapeutic target. Utilizing multi-omics approaches, we rigorously analyzed four distinct mouse models, both with and without APPtg and ABCA7 expression, to simulate varied pathological and ABCA7-deficient states. Our results revealed amyloid-beta (Aβ) deposition as a catalyst for surging glutamatergic transmission. Notably, ABCA7 ablation exacerbated glutamatergic-induced neurotoxicity, attributed to diminished enzymatic activity related to neurotransmitter degradation and amplified expression levels of specific neurotransmitter transport proteins and receptor subunits, notably NMDA, AMPA, and GABAA. These findings furnish the first comprehensive description elucidating ABCA7’s amplification of neurotoxic effects through modulation of Glu-GABA neurotransmission systems in neurodegenerative contexts, primarily mediated by lipid interaction. The evidence underscores ABCA7’s imperative role in shaping future pharmacological strategies aimed at counteracting neurodegeneration precipitated by Glu-mediated neurotoxicity. This research advances the frontier for therapeutic exploration to ameliorate the deleterious neural consequences characteristic of neurodegenerative pathologies. Highlights Alterations within the ABCA7 transporter locus constitute the second most significant genetic predisposition factor for Alzheimer’s disease (AD), subsequent to the influence of the APOE4 allele. Excessive stimulation of glutamatergic neurotransmission culminates in excitotoxicity, leading to the gradual demise of neuronal populations due to pathological hyperactivity. In murine models with wild-type genetics, the absence of ABCA7 results in diminished functionality of both the glutamatergic and GABAergic neurotransmitter systems. Conversely, in mouse models engineered to mimic Alzheimer’s pathology, deficiency in ABCA7 exacerbates glutamate-induced neurotoxicity. During amyloid-β accumulation, the absence of ABCA7 correlates with an elevation in specific lipid levels, potentially contributing to neurodegenerative processes. From a therapeutic standpoint, pharmacological activation of ABCA7 may mitigate the neuronal death associated with glutamate overactivation in individuals afflicted by neurodegenerative disorders. Competing Interest Statement The authors have declared no competing interest. Footnotes REV2 after review, text and figures were revised. Abbreviations - Aβ - amyloid-β - AD - Alzheimer’s disease - AMPA - α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid - APP - amyloid-β precursor protein - APOE - apolipoprotein E - ABCA7 - ATP-binding cassette sub-family A member 7 - BBB - blood-brain barrier - CNS - central nervous system - CSF - cerebrospinal fluid - GABA - γ-aminobutyric acid - Glu - glutamate - GFAP - glial fibrillary acidic protein - Gln - glutamine - GWAS - genome-wide association studies - iGluR - ionotropic glutamate receptor - ISF - interstitial fluid - α-KG - α-ketoglutarate - LC-MS/MS - liquid chromatography with tandem mass spectrometry - LV - lateral ventricle - LTP - long-term potentiation - NCSTN - nicastrin - NMDA - N-Methyl-D-Aspartate - OPT - optic tract - PC - Phosphatidylcholine - PCA - Principal component analysis - PD - Parkinson’s disease - PE - Phosphatidylethanolamine - PICK-1 - Protein interacting with C-kinase - PLA2 - phospholipase A2 - PSEN1 - presenilin 1 - ROS - Reactive oxygen species - TCA - tricarboxylic acid