Alzheimer's genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis.
Overview
- Center for Brain Immunology and Glia (BIG), Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
- Physiology Graduate Program, University of Virginia, Charlottesville, VA, USA
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
Abstract
Recent genome-wide association studies have identified numerous Alzheimer’s disease (AD) risk genes enriched in microglia, including Crk-associated substrate (Cas) scaffold protein family member 4 (CASS4), which encodes the adaptor protein CASS4. Despite its strong genetic association with AD, the role of CASS4 in disease remains poorly understood. Here, we show that full-body Cass4 deletion in 5xFAD mice increases amyloid-β (Aβ) deposition, neuronal dystrophy, and cognitive deficits. Since microglia are the predominant brain-resident cells expressing Cass4, we investigated its role in microglial responses to Aβ pathology. Loss of CASS4 impaired microglial mobilization to Aβ plaques and reduced plaque compaction. Phosphoproteomic analysis of purified microglia revealed marked disruption of focal adhesion signaling following Cass4 deletion. Consistent with this, CASS4 deficiency abrogated in vivo microglial recruitment to injury and in vitro wound healing responses, two processes that are centrally orchestrated by focal adhesion biology. Together, these findings identify CASS4 as a critical regulator of microglial function and focal adhesion biology and suggest that CASS4 may represent a therapeutic target for AD.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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LukensLab
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Data
Datasets cited
- figshare:34238421, at figshare; found in “Data availability”
Data availability
The data underlying the figures are available in the published article and its online supplemental material. Single-nucleus sequencing data have been deposited in the GEO repository public website (accession number GSE348326). Source data have been uploaded to Figshare at the following DOI: 10.6084/
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 30 October 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 12 MeSH terms, 9 funders, 132 references.
Cite
This paper
Walsh, A. E., Davis, B. A., Samuels, J. D., Mills, W. A., Thanos, J. M., Johnson, A. M., Moore, K. A., Puchalski, M. A., Steacy, E. J., Wendell, B. W., Daugherty-Lopès, A., Shimpi, A. A., Eyo, U. B., & Lukens, J. R. (2026). Alzheimer's genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis. The Journal of experimental medicine, 223(12), e20260104. https://
BibTeX
@article{walsh2026alzhei
author = {Walsh, Adeline E. and Davis, Benjamin A. and Samuels, Joshua D. and Mills, William A. and Thanos, Jessica M. and Johnson, Alexis M. and Moore, Katelyn A. and Puchalski, Michael A. and Steacy, Eric J. and Wendell, Benjamin W. and Daugherty-Lopès, Amélie and Shimpi, Adrian A. and Eyo, Ukpong B. and Lukens, John R.},
title = {{Alzheimer's genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis}},
journal = {The Journal of experimental medicine},
year = {2026},
month = oct,
volume = {223},
number = {12},
pages = {e20260104},
publisher = {The Rockefeller University Press},
issn = {0022-1007},
doi = {10.1084/
url = {https://
pmid = {42944718},
pmcid = {PMC13712264}
}
RIS
TY - JOUR
AU - Walsh, Adeline E.
AU - Davis, Benjamin A.
AU - Samuels, Joshua D.
AU - Mills, William A.
AU - Thanos, Jessica M.
AU - Johnson, Alexis M.
AU - Moore, Katelyn A.
AU - Puchalski, Michael A.
AU - Steacy, Eric J.
AU - Wendell, Benjamin W.
AU - Daugherty-Lopès, Amélie
AU - Shimpi, Adrian A.
AU - Eyo, Ukpong B.
AU - Lukens, John R.
TI - Alzheimer's genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis
T2 - The Journal of experimental medicine
J2 - J Exp Med
PY - 2026
DA - 2026/
VL - 223
IS - 12
SP - e20260104
SN - 0022-1007
PB - The Rockefeller University Press
DO - 10.1084/
UR - https://
LA - en
ER -
CSL-JSON
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