Functional genomics of microglial phagocytosis for precision neuroimmune therapeutics

Project Summary Alzheimer's disease (AD) is characterized by amyloid plaques, Tau neurofibrillary tangles, and synapse loss. While amyloid targeting immunotherapies have shown some modest success, there is a critical unmet clinical need for more effective therapeutics as the prevalence of AD increases globally. Microglia, the brain resident macrophage, significantly influence all of the pathological hallmarks of the disease through phagocytosis, and many AD genetic risk factors are exclusively expressed by these immune cells. This project aims to develop the first in vivo CRISPR screening platform to identify genetic regulators of microglial phagocytosis in AD, focusing on (1) amyloid phagocytosis in combination with amyloid-targeting antibodies, (2) Tau phagocytosis via suppressor screens in microglia harboring rare genetic variants that prevent Tau aggregate spread, and (3) the discovery of regulators of microglial synapse phagocytosis to preserve cognitive function in AD mouse models. By leveraging recently developed methods for hematopoietic stem cell gene editing, barcoding, and microglial transplantation in AD models, this research will uncover novel therapeutic targets to enhance microglial function, potentially leading to more effective treatments. The insights gained will have broad implications for understanding the biology of tissue-resident macrophages and for diseases involving macrophage phagocytosis, including cancer and atherosclerosis.