Age-dependent brain proteome remodeling links Abca7 deficiency to insulin signaling and neuroinflammation in Alzheimers disease mice

Abstract

The human ABCA7 gene, which encodes ATP-binding cassette transporter A7 (ABCA7), is one of the strongest genetic risk factors for late-onset Alzheimers disease (AD), yet the molecular mechanisms linking ABCA7 deficiency to AD remain incompletely understood. Because impaired insulin signaling and neuroinflammation are increasingly recognized as key contributors to AD pathogenesis, and ABCA7 has been implicated in both metabolic and immune processes, we investigated whether ABCA7 deficiency is associated with alterations in these pathways using comparative brain proteomics. Whole-brain proteomes from wild-type, Abca7 knockout, AD model (APP), and APP- Abca7 knockout mice were analyzed at 50, 100, 150, and 200 days of age using label-free quantitative proteomics, followed by differential abundance analysis, gene ontology enrichment, subcellular localization analysis, protein-protein interaction network analysis, and comparison with human AD brain proteomic datasets. Comparative analyses identified age-dependent proteomic alterations associated with Abca7 deficiency, amyloid-beta pathology, and their interaction. Across all genotype comparisons, recurrently altered proteins and functional interaction networks consistently converged on insulin receptor and PI3K/AKT signaling, MAPK signaling, immune and complement pathways, vesicle trafficking and acidification, and the ubiquitin-proteasome system. Subcellular enrichment analysis further indicated preferential involvement of membrane-associated proteins, consistent with the established role of ABCA7 in membrane lipid transport and trafficking. Comparison with human AD proteomic data demonstrated substantial overlap while also identifying potentially novel proteins associated with Abca7deficiency in our mouse models. Together, these findings provide a systems-level characterization of the brain proteomic consequences of Abca7 deficiency and suggest that dysregulation of interconnected metabolic, immune, and vesicle-associated pathways may contribute to AD-related brain pathology.