Abi3S212F Alzheimer's disease variant alters plaque structure and disrupts microglia.

BACKGROUND: Genetic variants affecting microglial function can influence Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. The AD-associated ABI3S209F (Abi3S212F in mouse) variant regulates cytoskeletal dynamics, but its in vivo impact on pathology is unknown. METHODS: An Abi3S212F mouse was developed and crossed with two humanized amyloid beta (Aβ) models. Amyloid pathology, microglial survival, and remodeling were analyzed using confocal imaging, biochemical assays, spatial transcriptomics, and single-cell analyses across the lifespan. RESULTS: Abi3S212F produced a dysfunctional microglial state that reduced dense-core plaque compaction, selectively lowering dense-core burden without affecting diffuse or total Aβ. The variant also caused microglial loss via apoptosis and pyroptosis, requiring aging and human Aβ but occurring even without plaques, indicating plaque-independent vulnerability. Spatial transcriptomics revealed an age-dependent shift toward an Abi3-high state that predisposes microglia to degeneration. DISCUSSION: Abi3S212F produces microglial dysfunction and vulnerability, highlighting cytoskeletal and cell death pathways as therapeutic targets.