<i> Abi3 <sup>S212F</sup> </i> Alzheimer's disease variant alters plaque structure and disrupts microglia
BACKGROUND: in mouse) variant regulates cytoskeletal dynamics, but its in vivo impact on pathology is unknown. METHODS: 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: 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: produces microglial dysfunction and vulnerability, highlighting cytoskeletal and cell death pathways as therapeutic targets.
Authors
- Min Sung Gee (ORCID: https://orcid.org/0000-0002-7276-6086)
- Kai‐Xuan Shi
- Heidi Yahan Liang (ORCID: https://orcid.org/0000-0002-6190-9723)
- Zechuan Shi (ORCID: https://orcid.org/0000-0002-2844-5816)
- Yueh-Hao Lu
- Karina Genaro (ORCID: https://orcid.org/0000-0001-6450-5778)
- Shimako Kawauchi (ORCID: https://orcid.org/0000-0002-8577-4763)
- Amber D. Walker
- A Mortazavi (ORCID: https://orcid.org/0000-0002-4259-6362)
- Giedre Milinkeviciute (ORCID: https://orcid.org/0000-0003-2527-3892)
- Grant R. MacGregor (ORCID: https://orcid.org/0000-0001-7598-9501)
- Katie O'Gara
- Shuling Wang (ORCID: https://orcid.org/0000-0002-3517-2588)
- Zachary A. Pashkutz
- Frank M. LaFerla
- Vivek Swarup
- Christiana Prekopa
- Maigan L. A. Wong
- Sherilyn D. Collins
- Celia Da Cunha
- Andrea J. Tenner
- Kim N. Green
- Jenna A. Sanchez
- Jonathan Neumann
- Duc M. Duong
- Nicholas T. Seyfried
- Kate I. Tsourmas
- Angela Gomez‐Arboledas
- Nellie Kwang
- Claire A. Butler
Institutions
- Emory University (US)
- University of California, Irvine (US)
- AIDS Research Consortium of Atlanta (US)
- Irvine University (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2026-05-01
- DOI
- https://doi.org/10.1002/alz.71452
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute on Aging
- Chao Family Comprehensive Cancer Center