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- Title
The Alzheimer's disease-associated protective Plcγ2-P522R variant promotes immune functions.
- Authors
Takalo, Mari; Wittrahm, Rebekka; Wefers, Benedikt; Parhizkar, Samira; Jokivarsi, Kimmo; Kuulasmaa, Teemu; Mäkinen, Petra; Martiskainen, Henna; Wurst, Wolfgang; Xiang, Xianyuan; Marttinen, Mikael; Poutiainen, Pekka; Haapasalo, Annakaisa; Hiltunen, Mikko; Haass, Christian
- Abstract
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) 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 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 and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice. Conclusion: The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.
- Subjects
ETIOLOGY of diseases; INFLAMMATION; IMMUNOLOGIC diseases; ALZHEIMER'S disease; CELL physiology; PHAGOCYTOSIS; MICROGLIA
- Publication
Molecular Neurodegeneration, 2020, Vol 15, Issue 1, pN.PAG
- ISSN
1750-1326
- Publication type
Article
- DOI
10.1186/s13024-020-00402-7