The Alzheimer's disease-associated protective Plcγ2-P522R variant promotes immune functions
Mari Takalo1, Rebekka Wittrahm1, Benedikt Wefers2,3
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
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.
Insights
A rare genetic variant in the PLCG2 gene (p.P522R) protects against Alzheimer's disease (AD) by enhancing microglial function and inflammation. This discovery opens new therapeutic avenues for AD targeting the TREM2-PLCγ2 pathway.
Area of Science:
- Neuroimmunology
- Genetics of Neurodegeneration
- Innate Immune System
Background:
- Microglia-specific genetic variants are linked to neurodegenerative diseases like Alzheimer's disease (AD).
- A rare variant in the PLCG2 gene (p.P522R) is associated with reduced AD risk.
Purpose of the Study:
- To investigate the functional role of the protective PLCG2 p.P522R variant in immune cells.
- To assess the impact of this variant on microglial function and Alzheimer's disease pathogenesis.
Main Methods:
- Generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing.
- Performed functional analyses on macrophages and microglia-like cells from KI and wild-type (WT) mice.
- Utilized immunohistochemistry, brain mRNA sequencing, and positron emission tomography (PET) imaging.
Main Results:
- The P522R variant potentiates Phospholipase C gamma 2 (Plcγ2) enzyme activity, enhancing macrophage survival and inflammatory response.
- Overexpression of PLCγ2-P522R in microglia-like cells improved phagocytosis.
- KI mice showed enhanced microglial functions, indicated by brain mRNA signatures and PET imaging, without altering microglia number or morphology.
Conclusions:
- The AD-protective Plcγ2-P522R variant enhances microglial functions, particularly those associated with TREM2 signaling.
- Targeting the TREM2-PLCγ2 pathway offers a potential novel therapeutic strategy for Alzheimer's disease.
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