Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

Abstract

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimers disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and acts in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2 P522R variant, is a mild hypermorph that attenuates AD risk. We report the identification of a PLCG2 variant, PLCG2 M28L variant, associated with loss-of-function and confers increased AD risk. PLCG2 P522R variant attenuates disease in an amyloidogenic murine AD model, whereas PLCG2 M28L variant exacerbates the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2 M28L variant as a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

The crystal and cryo-EM structures of PLCγ2 reveal dynamic inter-domain recognitions in autoinhibition

“…Activity studies indicated that this variant modestly increases the enzymatic function of PLCγ2 [22][23][24] . Recent studies also suggest that a different missense variant of PLCγ2 (M28L) is associated with loss-of-function and an elevated risk for Alzheimer's disease 18,[25][26][27] .…”