Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Abi3S212F Alzheimer's disease variant alters plaque structure and disrupts microglia.
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Butler Claire A, Gee Min Sung, O'Gara Katie, Milinkeviciute Giedre, Da Cunha Celia, Kawauchi Shimako, Lu Yueh-Hao, Kwang Nellie, Tsourmas Kate I, Prekopa Christiana, Shi Zechuan, Liang Heidi Yahan, Collins Sherilyn D, Pashkutz Zachary A, Sanchez Jenna A, Shi Kai-Xuan, Walker Amber D, Wang Shuling, Wong Maigan L A, Genaro Karina, Neumann Jonathan, Gomez-Arboledas Angela, Duong Duc M, Seyfried Nicholas T, Tenner Andrea J, LaFerla Frank M, Mortazavi Ali, Swarup Vivek, MacGregor Grant R, Green Kim N
Аннотация
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.
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.