美国印第安纳大学医学院Gary E. Landreth课题组发现，磷脂酶C-γ2的遗传变异会改变小胶质细胞的表型和功能，并带来罹患阿尔茨海默病的不同风险。2023年9月1日，国际知名学术期刊《免疫》在线发表了这一成果。

据研究人员介绍，遗传关联研究表明，小胶质细胞免疫反应在阿尔茨海默病（AD）发病机制中起着至关重要的作用。磷脂酶C-γ-2（PLCG2）由小胶质细胞选择性表达，在许多免疫受体信号通路中发挥作用。在AD中，PLCG2在斑块相关的小胶质细胞中被特异性诱导。PLCG2的一种遗传变异PLCG2^P522R是一类轻度的超等位基因，可降低 AD 风险。

研究人员发现了一种功能缺失的PLCG2变异体PLCG2^M28L，它能增加AD风险。在淀粉样蛋白致病小鼠AD模型中，PLCG2^P522R减轻了疾病，而PLCG2^M28L则加重了与吞噬和Aβ清除改变相关的斑块负担。这些变体通过诱导不同的转录程序双向调节疾病病理，并且这些转录程序确定了与保护性或有害表型相关的小胶质细胞亚群。这些发现将PLCG2^M28L鉴定为一种潜在的AD风险变体，并证明PLCG2变体能在AD发病机制中以不同方式协调小胶质细胞的反应，而这些反应是可以治疗靶向的。

附：英文原文

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

Author: 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

Issue&Volume: 2023-09-01

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, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L 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 PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

DOI: 10.1016/j.immuni.2023.08.008

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00364-3