APOE in Choroid Plexus Function and Related Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly and has emerged as an escalating public health crisis within our aging population. Although recent anti-amyloid therapies have offered hope to treat individuals with early AD, the efficacy is limited along with safety concerns in some patients. As such, there is an urgent need to develop more effective treatment to prevent or cure this devastating disease. The apolipoprotein E (APOE) gene is the most important genetic risk factor for AD with the APOE4 gene form increases and APOE2 decreases AD risk compared to the most common APOE3. Studies from ours and other groups have demonstrated a direct effect of APOE4 in accelerating the development of amyloids, the key pathological feature of AD. However, increasing evidence also supports additional effects of APOE4 in other Alzheimer’s-related pathways including brain vasculature and immune responses. Further, how APOE2 protects against AD is largely unclear. As such, our long-term goal is to explore APOE-targeted therapy by understanding how different APOE isoforms modulate diverse mechanisms of AD pathology and development. One of the important but less studied mechanisms is the effects of APOE on the functions of the choroid plexus (ChP), which is a highly vascularized tissue in the brain ventricles responsible for producing cerebrospinal fluid (CSF). Previous studies have shown that ChP enlargement is associated with AD progression. Importantly, ChP epithelial cells produce large amounts of APOE protein. As such, our specific goal for this project is to elucidate how different forms of APOE made by ChP differentially impact ChP function in CSF production and AD pathology and pathways. Our specific hypothesis is that ChP epithelial cell-expressed APOE4 is detrimental whereas APOE2 provides a protective advantage compared to APOE3, influencing CSF production, blood-CSF barrier integrity, and related brain cognition and AD pathology. We plan to test our hypothesis by examining how different forms of APOE affect the function of ChP epithelial cells using animal models and human cell-derived brain organoid models. Upon completion of these studies, we will acquire more comprehensive knowledge on how ChP-expressed APOE impacts brain functions and AD pathology in an APOE genotype-specific manner. This knowledge will help with rational design of therapeutic strategy targeting APOE in AD therapy in an APOE genotype-specific manner toward precision medicine.