The Alzheimer’s disease-associated protective Plcγ2 -P522R variant promotes beneficial microglial functions

Background Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) selectively expressed in microglia and macrophages was recently identified and shown to reduce the risk for AD. Methods To assess the role of this variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Results Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival, enhanced phagocytic activity, and increased acute inflammatory response of the KI cells. Enhanced phagocytosis was also observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Furthermore, the brain mRNA signature together with microglia-specific PET imaging indicated microglia activation in Plcγ2-P522R KI mice. Conclusion Thus, we have delineated cellular mechanisms of the protective Plcγ2-P522R variant, which provide further support for the emerging idea that activated microglia exert protective functions in AD. * Plcγ2 : phospholipase C gamma 2 Pip2 : phosphatidylinositol 4,5-bisphosphate Ip3 : 1,4,5-trisphosphate Dag : diacylglycerol Trem2 : Triggering receptor expressed on myeloid cells 2 Nfκb : nuclear factor kappa-light-chain-enhancer of activated B cells Mapk/Erk : mitogen-activated protein kinase Akt : protein kinase B KI : knock-in WT : wild type BMDM : bone marrow-derived macrophage Ip1 : inositol monophosphate LPS : lipopolysaccharide IFNγ : interferon gamma TNFα : tumor necrosis factor alpha IL-6 : interleukin-6 IL-1β : interleukin 1 beta NO : nitric oxide DAM : disease associated microglia