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

Increasing attention has been directed towards the perturbation of glutamate (Glu) and {gamma}-aminobutyric acid (GABA) homeostasis during the pathogenesis of Alzheimers 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 (A{beta}) 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 ABCA7s amplification of neurotoxic effects through modulation of Glu-GABA neurotransmission systems in neurodegenerative contexts, primarily mediated by lipid interaction. The evidence underscores ABCA7s 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. HighlightsO_LIAlterations within the ABCA7 transporter locus constitute the second most significant genetic predisposition factor for Alzheimers disease (AD), subsequent to the influence of the APOE4 allele. C_LIO_LIExcessive stimulation of glutamatergic neurotransmission culminates in excitotoxicity, leading to the gradual demise of neuronal populations due to pathological hyperactivity. C_LIO_LIIn murine models with wild-type genetics, the absence of ABCA7 results in diminished functionality of both the glutamatergic and GABAergic neurotransmitter systems. C_LIO_LIConversely, in mouse models engineered to mimic Alzheimers pathology, deficiency in ABCA7 exacerbates glutamate-induced neurotoxicity. C_LIO_LIDuring amyloid-{beta} accumulation, the absence of ABCA7 correlates with an elevation in specific lipid levels, potentially contributing to neurodegenerative processes. C_LIO_LIFrom a therapeutic standpoint, pharmacological activation of ABCA7 may mitigate the neuronal death associated with glutamate overactivation in individuals afflicted by neurodegenerative disorders. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/666774v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1491b86org.highwire.dtl.DTLVardef@ae3bb3org.highwire.dtl.DTLVardef@d1716dorg.highwire.dtl.DTLVardef@6dd7a2_HPS_FORMAT_FIGEXP M_FIG C_FIG