Abstract
BackgroundRecent 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.MethodsWe 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.ResultsPLCG2 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.ConclusionsThe 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.
Highlights
Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset Alzheimer’s disease (LOAD)
PLCγ2 is predominantly expressed in the bone marrow and lymphoid organs (Human Protein Atlas available from www.proteinatlas.org [11]), and phospholipase C-gamma 2 (PLCG2) variants cause inherited immune disorders designated as PLCG2-associated antibody deficiency and immune dysregulation (PLAID)
We found that Plcg2 mRNA mainly co-localizes with microglia markers in healthy brain tissue, as well as in microglia near amyloid plaques in an amyloid precursor protein (APP) mouse model of AD
Summary
Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset Alzheimer’s disease (LOAD). 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 PLCG2 belongs to the family of phospholipase C-gamma and encodes an enzyme (PLCγ2) that cleaves the membrane phospholipid PIP2 PLCγ2 shares high structural and mechanistic overlap with the other member of the PLCγ family, PLCγ1 [7] Both enzymes are important for regulation of specific responses of specialized cells of the immune system, they show different cell-type expression and are relevant in very different medical conditions [7]. PLCγ2 is predominantly expressed in the bone marrow and lymphoid organs (Human Protein Atlas available from www.proteinatlas.org [11]), and PLCG2 variants cause inherited immune disorders designated as PLAID (PLCG2-associated antibody deficiency and immune dysregulation [12] and APLAID (autoinflammatory PLAID [13])
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