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

Date Published: February 2, 2019

Publisher: BioMed Central

Author(s): 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.

http://doi.org/10.1186/s13195-019-0469-0

Abstract

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.

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.

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.

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.

The online version of this article (10.1186/s13195-019-0469-0) contains supplementary material, which is available to authorized users.

Partial Text

Alzheimer’s disease is the most common neurodegenerative disorder and the leading cause of dementia. Late onset AD is genetically complex, and known susceptibility loci only explain a proportion of disease heritability [1]. Large-scale genetic studies have led to the identification of several new susceptibility genes associated with LOAD. These genetic data, together with an analysis of biological pathways, implicate processes related to immune response in the etiology of LOAD and point to the immune system as a prime target for therapeutic approaches [2–4]. Amongst the newly discovered polymorphisms, rare variants in microglial-related genes including triggering receptor expression on myeloid cell-2 (TREM2), ABI family member 3 (ABI3), and phospholipase C-gamma-2 (PLCG2) have been described [5, 6]. Notably, the PLCG2 missense variant Pro522Arg (P = 5.38 × 10−10, OR = 0.68) was associated with decreased risk of LOAD [6].

Although single-cell transcriptomics of the human and mouse cortex suggest enrichment of PLCG2 transcripts in the microglia population, no spatial analysis has been described for human and mouse tissue so far. In this report, we characterized PLCG2 spatial expression in the human and mouse brain.

In summary, we show that PLCG2 is expressed in human and mouse brain microglia and that its expression is maintained in microglia in close proximity to plaques in the cerebral tissue of an APP mouse model. The rare-coding AD protective variant shows a small hypermorphic activity upon stimulation in various orthogonal cell-based assays. Further experiments will need to address the functional consequences of the protective variant on immune cell phenotype. However, these findings allow us to speculate that weak lifelong activation of PLCγ2 might confer protection against developing AD, and provide evidence that a limited activation of this enzyme may have a beneficial therapeutic effect. In comparison to previous studies which are aligned to the concept that suppressing microglial function may be beneficial in the setting of AD [49], the data described here, together with studies on TREM2 and other AD-associated variants, suggest that a different directionality may be therapeutically useful [6, 46, 50].

 

Source:

http://doi.org/10.1186/s13195-019-0469-0

 

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