AI Article Synopsis
- - The study identifies a rare genetic variant (PLCG2-P522R) linked to reduced risk for Alzheimer’s disease (AD) and investigates its role in immune cell functions through a genetically modified mouse model.
- - The PLCG2-P522R variant enhances macrophage functions, such as improved survival and inflammation response, and increases phagocytosis in microglia-like cells, suggesting enhanced microglial activity in the genetically modified mice.
- - The findings suggest that the PLCG2-P522R variant may promote protective immune responses in the brain via TREM2 signaling, highlighting its potential as a target for new AD therapies.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488484 | PMC |
| http://dx.doi.org/10.1186/s13024-020-00402-7 | DOI Listing |
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