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Open Access 01-12-2019 | Pityriasis Lichenoides Chronica | Research

Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph

Authors: Lorenza Magno, Christian B. Lessard, Marta Martins, Verena Lang, Pedro Cruz, Yasmine Asi, Matilda Katan, Jamie Bilsland, Tammaryn Lashley, Paramita Chakrabarty, Todd E. Golde, Paul J. Whiting

Published in: Alzheimer's Research & Therapy | Issue 1/2019

Abstract

Background

Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset Alzheimer’s disease (LOAD). Amongst these, a polymorphism in phospholipase C-gamma 2 (PLCG2) P522R has been reported to be protective against LOAD.

PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.

Methods

We assessed PLCG2 distribution in human and mouse brain tissue via immunohistochemistry and in situ hybridization. We transfected heterologous cell systems (COS7 and HEK293T cells) to determine the effect of the P522R AD-associated variant on enzymatic function using various orthogonal assays, including a radioactive assay, IP-One ELISA, and calcium assays.

Results

PLCG2 expression is restricted primarily to microglia and granule cells of the dentate gyrus. Plcg2 mRNA is maintained in plaque-associated microglia in the cerebral tissue of an AD mouse model. Functional analysis of the p.P522R variant demonstrated a small hypermorphic effect of the mutation on enzyme function.

Conclusions

The PLCG2 P522R variant is protective against AD. We show that PLCG2 is expressed in brain microglia, and the p.P522R polymorphism weakly increases enzyme function. These data suggest that activation of PLCγ2 and not inhibition could be therapeutically beneficial in AD. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.

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Title: Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Authors: Lorenza Magno
Christian B. Lessard
Marta Martins
Verena Lang
Pedro Cruz
Yasmine Asi
Matilda Katan
Jamie Bilsland
Tammaryn Lashley
Paramita Chakrabarty
Todd E. Golde
Paul J. Whiting
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Pityriasis Lichenoides Chronica
Alzheimer's Disease
Alzheimer's Disease
Published in: Alzheimer's Research & Therapy / Issue 1/2019
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/s13195-019-0469-0

2024 ASCO Annual Meeting

Springer Medicine

Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph

Abstract

Background

Methods

Results

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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