PT  - JOURNAL ARTICLE
AU  - Mari Takalo
AU  - Rebekka Wittrahm
AU  - Benedikt Wefers
AU  - Samira Parhizkar
AU  - Kimmo Jokivarsi
AU  - Teemu Kuulasmaa
AU  - Petra Mäkinen
AU  - Henna Martiskainen
AU  - Wolfgang Wurst
AU  - Xianyuan Xiang
AU  - Mikael Marttinen
AU  - Pekka Poutiainen
AU  - Annakaisa Haapasalo
AU  - Mikko Hiltunen
AU  - Christian Haass
TI  - The Alzheimer’s disease-associated protective <em>Plcγ2</em>-P522R variant promotes beneficial microglial functions
AID  - 10.1101/2020.04.08.031567
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.08.031567
4099  - http://biorxiv.org/content/early/2020/04/09/2020.04.08.031567.short
4100  - http://biorxiv.org/content/early/2020/04/09/2020.04.08.031567.full
AB  - 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.Plcγ2phospholipase C gamma 2Pip2phosphatidylinositol 4,5-bisphosphateIp31,4,5-trisphosphateDagdiacylglycerolTrem2Triggering receptor expressed on myeloid cells 2Nfκbnuclear factor kappa-light-chain-enhancer of activated B cellsMapk/Erkmitogen-activated protein kinaseAktprotein kinase BKIknock-inWTwild typeBMDMbone marrow-derived macrophageIp1inositol monophosphateLPSlipopolysaccharideIFNγinterferon gammaTNFαtumor necrosis factor alphaIL-6interleukin-6IL-1βinterleukin 1 betaNOnitric oxideDAMdisease associated microglia