Szatmari, E. M.; Moran, C.; Cohen, S. J.; Bashtovyy, D.; Jacob, A. L.; Bunner, W.; Phipps, M.; Stackman, R. W.; Yasuda, R. L.

ArfGAP, with dual PH domain-containing protein 1/Centaurin-(ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. An increased level of CentA1 and its association with amyloid plaques in the human Alzheimer\'s disease (AD) brain suggest a role for this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 KO mice with the J20 mouse model of AD. We evaluated the behavioral and neuropathological hallmarks of AD and the gene expression profiles in J20 and J20 crossed with CentA1 KO mice (J20 x CentA1 KO) to determine the impact of eliminating CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris Water Maze test showed significant impairment in J20 mice, which was rescued in J20 x CentA1 KO. Moreover, neuropathological hallmarks of AD, such as deposits of amyloid plaques and neuroinflammation, were significantly reduced in J20 x CentA1 KO. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes (DEGs) between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20 x CentA1 KO vs J20) were anti-correlated with changes caused by APP overexpression (J20 vs WT), consistent with the rescues of J20 phenotypes by CentA1 KO. 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.