Identification and Quantitation of Novel ABI3 Isoforms Relative to Alzheimer’s Disease Genetics and Neuropathology
Open accessAbstract
Elucidating the actions of genetic polymorphisms associated with the risk of Alzheimer’s disease (AD) may provide novel insights into underlying mechanisms. Two polymorphisms have implicated ABI3 as a modulator of AD risk. Here, we sought to identify ABI3 isoforms expressed in human AD and non-AD brain, quantify the more abundant isoforms as a function of AD genetics and neuropathology, and provide an initial in vitro characterization of the proteins produced by these novel isoforms. We report that ABI3 expression is increased with AD neuropathology but not associated with AD genetics. Single-cell RNAseq of APP/PS1 mice showed that Abi3 is primarily expressed by microglia, including disease-associated microglia. In human brain, several novel ABI3 isoforms were identified, including isoforms with partial or complete loss of exon 6. Expression of these isoforms correlated tightly with total ABI3 expression but were not influenced by AD genetics. Lastly, we performed an initial characterization of these isoforms in transfected cells and found that, while full-length ABI3 was expressed in a dispersed punctate fashion within the cytosol, isoforms lacking most or all of exon six tended to form extensive protein aggregates. In summary, ABI3 expression is restricted to microglia, is increased with Alzheimer’s neuropathology, and includes several isoforms that display a variable tendency to aggregate when expressed in vitro.
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ABI3 is highly abundant in both human AD brains and APP/PS1 mice.
“Consistent with previous scRNA‐seq studies, ABI3 is expressed predominantly in microglia and highly abundant in both human AD brains and APP/PS1 mice. 39 , 40”
From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [40]
Results §3.2 reports that ABI3 expression is modestly associated with AD neuropathology in human brain samples, while §3.3 reports robust Abi3 expression in APP/PS1 mouse microglia, especially disease-associated microglia. These findings support expression in both settings, but do not establish that ABI3 is highly abundant throughout human AD brains or APP/PS1 mice. (LLM, conf=0.83)
Experimental — accuracy not yet measuredABI3 is a microglia-enriched gene.
“ABI3 is a microglia-enriched gene (16, 18, 19).”
From The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies (2023) · cites this paper as [18]
ABI3 is highly expressed in microglia.
“ABI3 is highly expressed in microglia162,163 (Fig. 1c and Table 1), and ABI3 expression is increased in postmortem AD brains162,164.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [162]
ABI3 expression is increased in postmortem AD brains.
“ABI3 is highly expressed in microglia162,163 (Fig. 1c and Table 1), and ABI3 expression is increased in postmortem AD brains162,164.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [162]
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Cites
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Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics
Podleśny-Drabiniok, A., Marcora, E., & Goate, A. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.002 · Cited by 211 · see citing works
Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease
Satoh, J.-I., Kino, Y., Yanaizu, M., Tosaki, Y., Sakai, K., Ishida, T., & Saito, Y. (2017) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2017.01073 · Cited by 55 · see citing works
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Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways
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The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies
Karahan, H., Smith, D. C., Kim, B., McCord, B., Mantor, J., John, S. K., Al-Amin, M. M., Dabin, L. C., & Kim, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1102530 · Cited by 20 · see citing works
“ABI3 is a microglia-enriched gene (16, 18, 19).”
The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
Li, S., Lu, J., Zeng, K., Lu, X., Zhang, J., Feng, S., Liang, C., Cai, Y., Yao, S., Huang, Q., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71812
- Authors
- Turner, A. K., Shaw, B. C., Simpson, J. F., & Estus, S.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Estus, Steven
- Venue
- Genes
- Publisher
- MDPI AG
- Published
- 2022-09-08
- Volume
- 13
- Issue
- 9
- Pages
- 1607
- ISSN
- 2073-4425 (ISSN-L)
- PMC
- PMC9498898
- OpenAlex
- W4296137208
- Cited by
- 7
- References
- 9
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 4
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Genes (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (RF1AG059717, R21AG068370, F99NS120365)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ABI3, Alzheimer's disease, alternative splicing, protein isoforms, exon 6 deletion, microglia, disease-associated microglia, APP/PS1 mice, protein aggregation, genetic polymorphism, neuropathology, single-cell RNA sequencing
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Nervous System Diseases, Microglia, Protein Isoforms, Adaptor Proteins, Signal Transducing, Mice, Protein Aggregates
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