| First Author | Takalo M | Year | 2020 |
| Journal | Mol Neurodegener | Volume | 15 |
| Issue | 1 | Pages | 52 |
| PubMed ID | 32917267 | Mgi Jnum | J:307714 |
| Mgi Id | MGI:6724453 | Doi | 10.1186/s13024-020-00402-7 |
| Citation | Takalo M, et al. (2020) The Alzheimer's disease-associated protective Plcgamma2-P522R variant promotes immune functions. Mol Neurodegener 15(1):52 |
| abstractText | 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 Plcgamma2-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 Plcgamma2 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 PLCgamma2-P522R, but not in PLCgamma2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcgamma2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcgamma2-P522R KI mice. Conclusion: The AD-associated protective Plcgamma2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCgamma2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD. |
