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The Role of APOE in Microglia Regulation in Neurodegeneration

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Microglia, the primary immune cells and the sensors of the brain, play a pivotal role in the maintenance of brain homeostasis, but lose their functionality during the course of aging and neurodegenerative diseases. There is a gap in our knowledge about how microglial function is maintained in healthy brain and how and why it is prone to dysregulation in Alzheimer’s disease. There is also a lack of understanding of how the prominent genetic risk factor, APOE, is involved in microglia regulation and function. Human APOE has three common alleles, and the e4 allele is the major genetic risk factor for sporadic late-onset AD; its impact is even greater on women than men. The functional mechanisms underlying the genetic association of APOE4 with AD remain elusive. One mechanism by which APOE influences AD risk is by affecting amyloid beta clearance and accumulation. However, whether APOE directly regulates microglia functions in AD has not been investigated. This application will investigate the role of APOE in microglia as potential therapeutic targets of AD. Since APOE4 is the major risk factor of the disease, we will study the role of APOE4 in microglia regulation by employing novel tools, including new mouse models and techniques to specifically target APOE in order to restore microglia-mediated protein clearance and brain function in animal models of AD.