The Alzheimer's disease-associated protective Plcγ2-P522R variant promotes immune functions.
Mol Neurodegener. 2020 Sep 11;15(1):52. doi: 10.1186/s13024-020-00402-7. PMID: 32917267.
|Authors/Editors:||Takalo M, Wittrahm R, Wefers B, Parhizkar S, Jokivarsi K, Kuulasmaa T, Mäkinen P, Martiskainen H, Wurst W, Xiang X, Marttinen M, Poutiainen P, Haapasalo A, Hiltunen M, Haass C.|
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.