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 thePLCG2gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. Methods To assess the role of the protective variant in the context of immune cell functions, we generated a Plc gamma 2-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 Plc gamma 2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLC gamma 2-P522R, but not in PLC gamma 2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plc gamma 2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plc gamma 2-P522R KI mice. Conclusion The AD-associated protective Plc gamma 2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLC gamma 2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.
FörderungenEmil Aaltonen Foundation Academy of Finland Sigrid Juselius Foundation Strategic Neuroscience Funding of the University of Eastern Finland JPco-fuND2 2019 Personalised Medicine for Neurodegenerative Diseases Horizon 2020 Framework Programme of the European Union (Marie Sklodowska Curie grant) Orion Research Foundation Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology