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

Full-body Cass4 deletion in 5xFAD mice increases amyloid-β (Aβ) deposition, neuronal dystrophy, and cognitive deficits, linking CASS4 to AD pathology in this model.

• Why it matters: Although CASS4 is strongly genetically associated with Alzheimer’s disease and enriched in microglia, its functional role in disease mechanisms is poorly understood.
• What they did: The study used full-body Cass4 deletion in 5xFAD mice and assessed microglial responses to Aβ plaques, including mobilization and plaque compaction, plus phosphoproteomics of purified microglia.
• The result: Cass4 loss impaired microglial mobilization to Aβ plaques and reduced plaque compaction, disrupted focal adhesion signaling, and abrogated in vivo microglial recruitment to injury and in vitro wound healing responses, suggesting CASS4 as a therapeutic target.