PROJECT SUMMARY Alzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial-mediated immune response. Genetic studies have demonstrated that many of the genes that confer altered risk for AD are those involved in the innate immune response and are expressed primarily in microglia, including phospholipase C gamma 2 (PLCG2). PLCG2 is a critical signaling element for a variety of immune receptors and is a key regulatory hub gene for immune signaling. The primary objective of this proposal is to determine the role of PLCG2 in AD pathogenesis. GWAS studies have demonstrated that the PLCG2 P522R variant is associated with reduced AD risk. Our laboratory has identified a novel SNP (rs617749044) associated with elevated AD risk encoding the PLCG2 M28L variant. The overall objectives in this application are to elucidate the effect of these PLCG2 variants on AD pathogenesis using rodent models of AD and dissect the molecular mechanisms by which PLCG2 variants alter microglia function. The hypotheses are that the M28L variant is a loss of function allele, and conversely the P522R is protective with respect to AD pathogenesis in our murine models. The experiments proposed in this application are entirely novel and allow, for the first time, a unique, comprehensive analysis of an AD risk gene whose genetic variants confer both protection and risk for AD. Preliminary data generated by the applicant suggests that in a rodent model of AD, the M28L variant had accelerated and exacerbated disease related pathology and conversely the P522R variant appeared to attenuate disease severity and progression. The hypotheses will be tested by pursuing three specific aims: 1) Determine AD-related phenotypes altered by loss and gain of function PLCG2 variants in an amyloidogenic model of AD; 2) Identify molecular signatures and pathways in microglia that are associated with protective or risk PLCG2 variants in an amyloidogenic model of AD; and 3) Evaluate the mechanisms through which PLCG2 variants affect intracellular signaling in microglia. These studies are essential prerequisites for the development of PLCG2-directed therapeutics.