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CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. CentA1 upregulation and association with amyloid plaques in the human Alzheimer's disease (AD) brain suggest the role of this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 knock-out (KO) mice with the J20 mouse model of AD. We evaluated AD-associated behavioral and neuropathological hallmarks and gene expression profiles in J20 and J20 crossed with CentA1 KO (J20xKO) male mice 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 J20xKO mice. Moreover, neuropathological hallmarks of AD, such as amyloid plaque deposits and neuroinflammation, were significantly reduced in J20xKO mice. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20xKO vs J20) were anticorrelated with changes caused by APP overexpression (J20 vs wild type), consistent with rescue of J20 phenotypes by CentA1 KO. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes in this model and that targeting CentA1 signaling might have therapeutic potential for AD prevention or treatment.<\/jats:p>","DOI":"10.1523\/eneuro.0063-25.2025","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T18:50:12Z","timestamp":1763405412000},"page":"ENEURO.0063-25.2025","update-policy":"https:\/\/doi.org\/10.1523\/eneuro.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Lack of ADAP1\/Centaurin-\u03b11 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer's Disease"],"prefix":"10.1523","volume":"12","author":[{"given":"Erzsebet M.","family":"Szatmari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey","family":"Moran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah 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