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Updated: May 8, 2026

Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Abi3S212F Alzheimer's disease variant alters plaque structure and disrupts microglia
Claire A Butler1,2, Min Sung Gee1,2, Katie O'Gara1
1Department of Neurobiology and Behavior, University of California, Irvine, California, USA.
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.
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