Alzheimer’s disease (AD) is a progressive and debilitating dementia with inadequate treatment options, presenting an urgent need for novel therapeutic strategies. One leading disease hallmark of AD is the buildup of extracellular protein aggregates called amyloid beta plaques. Microglia, the major immune cells in the brain, play an important role in AD progression by limiting amyloid beta plaque burden. However, our understanding of the underlying mechanism of microglial regulation of plaque burden is incomplete. Microglia sense their environment through a protein type called receptors that are expressed on their surface. One such receptor is ADGRG1 (also called GPR56). ADGRG1 is expressed only in microglia and not in their peripheral counterparts called macrophages. Our preliminary study results show that deleting microglial ADGRG1 impairs microglia’s ability to clear amyloid beta. The goal of this research proposal is to investigate how microglial ADGRG1 regulates amyloid beta clearance. To accomplish this, we will first characterize the ADGRG1-dependent microglial response to amyloid deposition in both mouse AD models and human AD brains. Next, we will uncover the mechanism(s) by which microglial ADGRG1 regulates amyloid beta clearance. The success of the proposed research will not only advance our understanding of microglial mechanisms in AD progression but also uncover potential novel therapeutic targets.
