A Role for CASS4 and Microglial Focal Adhesion Signaling in Alzheimer's Disease Pathogenesis 33 views

Alzheimer’s disease (AD) is a neurological disorder that is classically defined by the presence of amyloid beta (Aβ) plaques and tau tangles in the brain. Recent genomic studies have also identified a role for microglia, the brain’s resident immune cell, in AD risk and pathology. Microglia play an important role in neuroinflammation, Aβ plaque containment, tau seeding and propagation, and eventual neuronal loss during disease. Many genes that have been linked to a heightened risk of developing AD are primarily expressed by microglia. This has led to increased interest and research in these cells to better understand how they impact disease pathology and whether they could be viewed as a therapeutic target to treat AD in the future. In this dissertation, we advance the understanding of how the AD genetic risk factor CASS4, which is expressed primarily by microglia, impacts disease onset and progression in two mouse models of AD. In addition to investigating CASS4 in the context of previously defined roles for microglia, such as plaque containment and phagocytosis, we also investigate areas that are relatively understudied in microglia, such as focal adhesion signaling. Understanding how microglia modulate cellular responses to neurodegenerative pathology may ultimately lead to novel treatments for disease. Utilizing the 5xFAD mouse model of amyloidosis, we describe the effect of CASS4 deletion on Aβ plaque load and mouse cognitive function. We further investigate how CASS4 impacts the ability of microglia to form close interactions with Aβ plaques. We also show that loss of CASS4 leads to impaired microglial responses to laser injury and cytokines and that Cass4 deletion alters focal adhesion-related pathways. These findings uncover a novel role for the risk factor CASS4 in microglial biology during amyloidosis and may aid in understanding the complex role of microglia in response to amyloid-driven disease. Additional studies outlined in this dissertation focus on the role of CASS4 in a tauopathy context. Using the PS19 mouse model, we observe that loss of CASS4 improves learning and memory and molecular hallmarks of microgliosis in the brain. Altogether, these findings reaffirm that AD is a complex disease and that microglia may have different functions in the brain depending on which pathological protein aggregate is present. Our work contributes to a more complete understanding of microglial function in the degenerating brain.

PHD (Doctor of Philosophy)

Alzheimer’s disease; CASS4; microglia; neurodegenerative disease; neuroimmunology; focal adhesion

English

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2026-10-16