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The AD\u2010associated\n \n ABI3\n S209F<\/jats:sup>\n <\/jats:italic>\n (\n \n Abi3\n S212F<\/jats:sup>\n <\/jats:italic>\n in mouse) variant regulates cytoskeletal dynamics, but its in vivo impact on pathology is unknown.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n An\n \n Abi3\n S212F<\/jats:sup>\n <\/jats:italic>\n mouse was developed and crossed with two humanized amyloid beta (A\u03b2) models. Amyloid pathology, microglial survival, and remodeling were analyzed using confocal imaging, biochemical assays, spatial transcriptomics, and single\u2010cell analyses across the lifespan.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n \n Abi3\n S212F<\/jats:sup>\n <\/jats:italic>\n produced a dysfunctional microglial state that reduced dense\u2010core plaque compaction, selectively lowering dense\u2010core burden without affecting diffuse or total A\u03b2. The variant also caused microglial loss via apoptosis and pyroptosis, requiring aging and human A\u03b2 but occurring even without plaques, indicating plaque\u2010independent vulnerability. Spatial transcriptomics revealed an age\u2010dependent shift toward an\n Abi3\u2010<\/jats:italic>\n high state that predisposes microglia to degeneration.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION:<\/jats:title>\n \n \n Abi3\n S212F<\/jats:sup>\n <\/jats:italic>\n produces microglial dysfunction and vulnerability, highlighting cytoskeletal and cell death pathways as therapeutic targets.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/alz.71452","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T03:55:13Z","timestamp":1778126113000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\n Abi3\n S212F<\/sup>\n <\/i>\n Alzheimer's disease variant alters plaque structure and disrupts microglia"],"prefix":"10.1002","volume":"22","author":[{"given":"Claire A.","family":"Butler","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Behavior University of California Irvine 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