Recent genome-wide association studies have pegged a rare coding variant of the Abi family 3 gene to higher risk of sporadic Alzheimer’s disease (Sims et al., 2017; Conway et al., 2018; Olive et al., 2020). A regulator of the actin cytoskeleton, Abi3 supports cell migration and phagocytosis (Moraes et al., 2017). The gene is highly expressed in microglia but its role there is unknown (Satoh et al., 2017). 

  • A rare coding variant of Abi3 increases risk of AD.
  • Knocking out Abi3 increases Aβ accumulation, neuroinflammation in mice.
  • Abi3 knockout microglia were DAM-like in their gene expression, but lethargic.

In the November 3 Science Advances, researchers led by Jungsu Kim, Indiana University School of Medicine, Indianapolis, reported that microglia lacking Abi3 were sluggish in going about their janitorial functions. 5xFAD mice lacking Abi3 had fewer microglia surrounding plaques, and accumulated more Aβ. When cultured, microglia lacking Abi3 migrated to plaques less vigorously, though their phagocytosis seemed largely unimpeded. The authors believe that apathetic microglia may drive Aβ accumulation in these knockouts, and that the AD variant causes a loss of physiological Abi3 function. “Even if Abi3 is not changing Aβ clearance or phagocytosis, impairing microglial migration can have a huge impact on disease,” first author Hande Karahan told Alzforum.

To suss out Abi3’s function in microglia, Karahan crossed 5xFAD mice with mice expressing one or no copies of Abi3. Compared to controls, 8-month-old knockout pups had twice as much cortical Aβ40 and Aβ42, 1.5 times more hippocampal amyloid, and 1.5 times as many cortical/hippocampal plaques (see image below). Heterozygous Abi3 knockouts fell in the middle, showing a gene-dosing effect. In hippocampal slices from Abi3 knockouts, long-term potentiation was stifled, indicating faulty synaptic function.

No Abi3, Much Amyloid. 5xFAD mice without this microglial cytoskeleton remodeler (right) had more 82E1-positive (top) and X34-positive plaques (bottom) than did 5xFAD mice expressing Abi3 normally (left). [Courtesy of Karahan et al., Science Advances, 2021.]

5xFAD mice with or without Abi3 had equivalent numbers of microglia; however, fewer of these cells surrounded plaques in knockout brains, suggesting Abi3 is needed for microglial motility toward Aβ aggregates (image below). A similar effect also occurs in TREM2 knockout mice, leading the authors to speculate that TREM2 might be an upstream regulator of ABI3 (May 2016 news). 

What about phagocytosis? The scientists knocked down the Abi3 gene in mouse microglia cultures, then added oligomeric Aβ42. The cells engulfed the same amount of Aβ regardless of Abi3 expression, hinting that phagocytosis per se was intact, at least in vitro.

To learn whether Abi3 influences other processes, as well, the researchers sequenced RNA of single cells from cortical tissue of gene knockouts and controls. Among the many differentially expressed genes in this preparation, those involved in autophagy, lipid metabolism, and the complement system were the most upregulated, highlighting an altered immune response in the knockouts over the 5xFAD mice themselves.

Stuck in Place?. Compared to brain tissue from 5xFAD mice expressing Abi3 (top panels), fewer microglia (green) surround amyloid plaques (blue) in the brains of mice lacking Abi3 (bottom panels). [Courtesy of Karahan et al., Science Advances, 2021.]

To zoom in on microglia among the other brain-cell types, the scientists used a targeted scRNA-Seq assay that measures almost 400 immune genes. Then they identified microglial subpopulations and analyzed their likely function based on gene expression. In 5xFAD mice expressing Abi3, the main microglial subgroup appeared to be involved in metabolism, whereas in Abi3 knockouts the majority of microglia were involved in immune responses. Microglia from 5xFAD mice express some disease-associated microglia (DAM) genes, but microglia from knockouts expressed more of them. To the scientist's mind, this implied that Abi3 dysfunction may induce reactive DAM-like microglia.

Noting that knocking out a disease gene is but a first step in elucidating its function, Kim said he plans to study how the known AD Abi3 variant affects plaques and neuroinflammation by creating a mouse with this point mutation.—Chelsea Weidman Burke


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Research Models Citations

  1. 5xFAD (B6SJL)

News Citations

  1. Barrier Function: TREM2 Helps Microglia to Compact Amyloid Plaques

Paper Citations

  1. . Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017 Sep;49(9):1373-1384. Epub 2017 Jul 17 PubMed.
  2. . ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans. Mol Neurodegener. 2018 Oct 11;13(1):53. PubMed.
  3. . Examination of the Effect of Rare Variants in TREM2, ABI3, and PLCG2 in LOAD Through Multiple Phenotypes. J Alzheimers Dis. 2020;77(4):1469-1482. PubMed.
  4. . ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway. Oncotarget. 2017 Sep 15;8(40):67769-67781. Epub 2017 Jun 29 PubMed.
  5. . Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease. Intractable Rare Dis Res. 2017 Nov;6(4):262-268. PubMed.

Further Reading


  1. . The association of clinical phenotypes to known AD/FTD genetic risk loci and their inter-relationship. PLoS One. 2020;15(11):e0241552. Epub 2020 Nov 5 PubMed.
  2. . Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease. Transl Psychiatry. 2019 Jan 31;9(1):55. PubMed.
  3. . Author Correction: Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation. Sci Rep. 2021 Sep 9;11(1):18377. PubMed.
  4. . F-actin-dependent regulation of NESH dynamics in rat hippocampal neurons. PLoS One. 2012;7(4):e34514. Epub 2012 Apr 4 PubMed.
  5. . NESH regulates dendritic spine morphology and synapse formation. PLoS One. 2012;7(4):e34677. Epub 2012 Apr 2 PubMed.
  6. . The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun Signal. 2015 Oct 1;13:41. PubMed.
  7. . Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model. Mol Neurodegener. 2015 Mar 19;10:12. PubMed.

Primary Papers

  1. . Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis. Sci Adv. 2021 Nov 5;7(45):eabe3954. Epub 2021 Nov 3 PubMed.