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Alzheimer's disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Lorenza Magno1, Christian B Lessard2, Marta Martins3,4
1UCL Alzheimer's Research UK, Drug Discovery Institute, London, UK. l.magno@ucl.ac.uk.
Alzheimer'S Research & Therapy
|February 4, 2019
Summary
A protective variant in phospholipase C-gamma 2 (PLCG2) is linked to late-onset Alzheimer's disease (LOAD). This study shows PLCG2 is in brain microglia and the variant weakly enhances enzyme function, suggesting activation may be therapeutic.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Genome-Wide Association Studies (GWAS) reveal rare variants in immune genes linked to late-onset Alzheimer's disease (LOAD).
- A specific polymorphism in phospholipase C-gamma 2 (PLCG2) P522R shows a protective effect against LOAD.
- PLCG2, highly expressed in the hematopoietic system, plays a role in immune cell regulation, with certain mutations causing autoinflammation.
Purpose of the Study:
- To investigate the expression and function of PLCG2 in the brain, particularly in relation to Alzheimer's disease.
- To determine the impact of the protective P522R variant on PLCG2 enzymatic activity.
Main Methods:
- Immunohistochemistry and in situ hybridization were used to assess PLCG2 distribution in human and mouse brain tissue.
- Heterologous cell systems (COS7 and HEK293T) were transfected to analyze the P522R variant's effect on enzymatic function.
- Orthogonal assays, including radioactive assays, IP-One ELISA, and calcium assays, were employed to measure enzyme activity.
Main Results:
- PLCG2 expression was found to be restricted mainly to microglia and granule cells of the dentate gyrus.
- Plcg2 mRNA was detected in plaque-associated microglia in an Alzheimer's disease mouse model.
- Functional analysis of the P522R variant indicated a minor hypermorphic effect on enzyme function.
Conclusions:
- The PLCG2 P522R variant confers protection against Alzheimer's disease.
- PLCG2 is expressed in brain microglia, and the P522R polymorphism results in a slight increase in enzyme function.
- These findings suggest that activating PLCγ2, rather than inhibiting it, could be a beneficial therapeutic strategy for AD, targeting microglia function.