Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer's Disease

ArfGAP, with dual PH domain-containing protein 1/Centaurin-1 (ADAP1CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. ADAP1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the dynamics of the actin cytoskeleton. An increased level of ADAP1 and its association with amyloid plaques in the human Alzheimers disease (AD) brain suggest a role for this protein in AD progression. To understand the role of ADAP1/CentA1 in neurodegeneration, we crossbred CentA1 KO mice with the hAPP-J20 mouse model of AD (J20 x CentA1 KO). We then evaluated the gene expression profile and the behavioral and neuropathological hallmarks of AD to determine the impact of eliminating ADAP1/CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris Water Maze test showed significant impairment in J20 mice, which was rescued by the deletion of CentA1. Neuropathological hallmarks of AD, such as deposits of amyloid plaques and neuroinflammation, were significantly reduced in the AD model mice with CentA1 KO background. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes (DEGs) between genotypes, by employing transcriptome profiling with Nanostring nCounter Neuropathology and Neuroinflammation panels. We found significant upregulation of genes associated with apoptosis and gliosis in the brain of J20 mice. However, many of these genes, including the pro-apoptotic gene, Bid, were restored in the brains of J20 x CentA1 KO mice compared to J20 mice. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes and that targeting CentA1 signaling at mitochondria might have therapeutic potential for AD prevention or treatment. SIGNIFICANCE STATEMENTADAP1/Centaurin-1 (CentA1) is highly enriched in the brain and increased CentA1 level has been linked to Alzheimers disease (AD). However, the precise role of ADAP1 in the pathogenesis of AD is poorly understood. We found that genetic deletion of CentA1 in the AD model mice rescues the pathological hallmarks of AD, including loss of dendritic spines in the hippocampus, amyloid plaque deposition, neuroinflammation and spatial memory deficits. Transcriptome analysis of forebrain samples using NanoString nCounter panels for 880 genes, identified the pro-apoptotic protein, Bid, with significantly reduced expression in the J20 mice on ADAP1 KO background. These findings point towards a role of ADAP1 in the activation of the mitochondrial pathways of death associated with the progression of neurodegeneration.