Project Summary/Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disease with virtually no therapeutic options to reverse its pathology. Glial cells, including microglia, play critical roles in brain homeostasis and disease progression. GPR56 (also called ADGRG1 ), an adhesion G protein-coupled receptor (aGPCR), is one of the critical genes that define "true" microglia: Gpr56 is only expressed in yolk sac-derived microglia but not in fetal liver- and bone marrow-derived microglia-like cells, even after long-term adaptation in the CNS in vivo. Importantly, a recent study from Mathys et al. showed that GPR56 is one of the five genes upregulated in microglia in individuals dying with early-stage AD compared to those with no pathology or late-stage AD. Importantly, their data was generated from participants in a community-based cohort study, the Religious Order Study (ROS)/Rush Memory and Aging Project (MAP), collectively known as ROSMAP. Of those autopsied, the mean age was 89 years. This observation raises the possibility that individuals with upregulated microglial GPR56 survived to advanced age with mild AD pathology. To investigate the unexplored function of microglial GPR56 in AD progression, we generated a new AD mouse model, 5xFAD;Gpr56""";Cx3cr1-Cre'1-(AD-cKO) and 5xFAD;Gpr56+1';Cx3cr1-Cre+1 - (AD-control). Our preliminary showed: (1) a significant reduction in the number of microglia associated with amyloid plaques, (2) a drastic increase in plaque burden, (3) a reduction in NeuNpositive neurons, and (4) more severe dendritic dystrophy in AD-cKO mouse brains compared to AD-controls. Taken together, I hypothesize that microg/ial GPR56 limits AD pathological progression in both AD mouse models and human patients. To test this hypothesis, I will address the following aims: Aim 1 is to investigate the role of microglial GPR56 in restricting AD progression in the mouse model; Aim 2 is to determine cellular and molecular mechanism(s) underlying microglial GPR56 function in AD pathogenesis; and Aim 3 is to characterize GPR56 expression and GPR56-dependent cellular responses in control, mild cognitive impairment (MCI), and AD human brain tissues. In summary, the proposed research will reveal crucial information about the role of microglial GPR56 in AD pathology. The success of this study will extend our knowledge of both glial cells and aGPCRs, providing a novel therapeutic target for AD treatment