Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease

Andy P Tsai; Chuanpeng Dong; Peter Bor-Chian Lin; Adrian L Oblak; Gonzalo Viana Di Prisco; Nian Wang; Nicole Hajicek; Adam J Carr; Emma K Lendy; Oliver Hahn; Micaiah Atkins; Aulden G Foltz; Jheel Patel; Guixiang Xu; Miguel Moutinho; John Sondek; Qisheng Zhang; Andrew D Mesecar; Yunlong Liu; Brady K Atwood; Tony Wyss-Coray; Kwangsik Nho; Stephanie J Bissel; Bruce T Lamb; Gary E Landreth

doi:10.1016/j.immuni.2023.08.008

Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease

Immunity. 2023 Sep 12;56(9):2121-2136.e6. doi: 10.1016/j.immuni.2023.08.008. Epub 2023 Sep 1.

Authors

Andy P Tsai¹, Chuanpeng Dong², Peter Bor-Chian Lin³, Adrian L Oblak⁴, Gonzalo Viana Di Prisco⁵, Nian Wang⁴, Nicole Hajicek⁶, Adam J Carr⁷, Emma K Lendy⁸, Oliver Hahn⁹, Micaiah Atkins⁹, Aulden G Foltz⁹, Jheel Patel³, Guixiang Xu³, Miguel Moutinho³, John Sondek⁶, Qisheng Zhang¹⁰, Andrew D Mesecar⁸, Yunlong Liu¹¹, Brady K Atwood⁵, Tony Wyss-Coray⁹, Kwangsik Nho¹², Stephanie J Bissel¹³, Bruce T Lamb¹³, Gary E Landreth¹⁴

Affiliations

¹ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
³ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
⁹ Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹² Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: glandret@iu.edu.

Abstract

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2^P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2^M28L, that confers an increased AD risk. PLCG2^P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2^M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2^M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

Keywords: Alzheimer’s disease; P522R and M28L variant; amyloid pathology; microglia; microglia-plaque interactions; microglial uptake capacity; neuroinflammation; phospholipase C-gamma-2; synaptic function; transcriptional programs.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Animals
Genetic Association Studies
Mice
Microglia
Phagocytosis / genetics
Phenotype
Phospholipase C gamma* / genetics
Phospholipase C gamma* / metabolism
Plaque, Amyloid

Substances

Phospholipase C gamma
Plcg2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding