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Peer-reviewedCC BY 4.0The Journal of Experimental Medicine

Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis

  • Adeline E. Walsh1,2
  • Benjamin A. Davis1
  • Joshua D. Samuels1,3,4
  • William A. Mills1
  • Jessica M. Thanos1
  • Alexis M. Johnson1,3
  • Katelyn A. Moore1
  • Michael A. Puchalski1
  • Eric J. Steacy1,3
  • Benjamin W. Wendell1
  • Amélie Daugherty-Lopès1
  • Adrian A. Shimpi4
2 more authors
  • Ukpong B. Eyo1,3
  • John R. Lukens1,3
4 affiliations
  1. 1Center 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
  2. 2Physiology Graduate Program, University of Virginia, Charlottesville, VA, USA
  3. 3Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA
  4. 4Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
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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.

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Cite

BibTeXRIS
BibTeX
@article{walsh2026alzheimers,
  title = {{Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis}},
  author = {Adeline E. Walsh and Benjamin A. Davis and Joshua D. Samuels and William A. Mills and Jessica M. Thanos and Alexis M. Johnson and Katelyn A. Moore and Michael A. Puchalski and Eric J. Steacy and Benjamin W. Wendell and Amélie Daugherty-Lopès and Adrian A. Shimpi and Ukpong B. Eyo and John R. Lukens},
  journal = {The Journal of Experimental Medicine},
  year = {2026},
  month = oct,
  doi = {10.1084/jem.20260104},
  url = {https://doi.org/10.1084/jem.20260104},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis
AU  - Adeline E. Walsh
AU  - Benjamin A. Davis
AU  - Joshua D. Samuels
AU  - William A. Mills
AU  - Jessica M. Thanos
AU  - Alexis M. Johnson
AU  - Katelyn A. Moore
AU  - Michael A. Puchalski
AU  - Eric J. Steacy
AU  - Benjamin W. Wendell
AU  - Amélie Daugherty-Lopès
AU  - Adrian A. Shimpi
AU  - Ukpong B. Eyo
AU  - John R. Lukens
PY  - 2026
DA  - 2026/10/27
JO  - The Journal of Experimental Medicine
DO  - 10.1084/jem.20260104
UR  - https://doi.org/10.1084/jem.20260104
AB  - 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.
SN  - 0022-1007
SN  - 1540-9538
ER  -