Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia-like cells

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-10-09 DOI:10.1002/alz.70772

Logan M. Bedford, Kaylee D. Tutrow, Karly Hooper, Evan J. Messenger, Melody Hernandez, Bruce T. Lamb, Jason S. Meyer, Timothy I. Richardson, Stephanie J. Bissel

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Abstract

INTRODUCTION

Variants of phospholipase C gamma 2 (PLCG2), a key microglial immune signaling protein, are genetically linked to Alzheimer's disease (AD) risk. Understanding how PLCG2 variants alter microglial function is critical for identifying mechanisms that drive neurodegeneration or resiliency in AD.

METHODS

Induced pluripotent stem cell (iPSC) –derived microglia carrying the protective PLCG2^P522R or risk-conferring PLCG2^M28L variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function.

RESULTS

Protective PLCG2^P522R microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2^M28L microglia shared similarities with PLCG2^KO microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2^P522R microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis.

DISCUSSION

These findings demonstrate that PLCG2 variants drive distinct microglia transcriptomes that influence microglial functional responses that could contribute to AD risk and protection. Targeting PLCG2-mediated signaling may represent a powerful therapeutic strategy to modulate neuroinflammation.

Highlights

The impact of Alzheimer's disease protective- and risk-associated variants of phospholipase C gamma 2 (PLCG2) on the transcriptome and function of induced pluripotent stem cell (iPSC) –derived microglia was investigated.
PLCG2 risk variant microglia exhibited a basal transcriptional profile similar to PLCG2-deficient microglia but significantly different from isotype control and the transcriptionally similar PLCG2 protective variant microglia.
PLCG2 risk variant and PLCG2-deficient microglia show decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2).
The differential transcriptional pathways of protective and risk-associated PLCG2 variant microglia functionally affect proliferation, apoptosis, and immune response.
Protective PLCG2 microglia show resilience to apoptosis and increased cytokine/chemokine secretion upon exposure to lipopolysaccharide (LPS).

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阿尔茨海默病相关PLCG2变异改变人诱导多能干细胞衍生的小胶质样细胞的小胶质状态和功能。

磷脂酶C γ 2 （PLCG2）是一种关键的小胶质免疫信号蛋白，其变异与阿尔茨海默病（AD）的风险有遗传关系。了解PLCG2变异体如何改变小胶质细胞功能对于确定阿尔茨海默病中驱动神经变性或恢复的机制至关重要。方法诱导多能干细胞（iPSC）衍生的小胶质细胞携带PLCG2P522R或PLCG2M28L变异，或PLCG2缺失，以确定对小胶质细胞转录组和功能的影响。结果保护性PLCG2P522R小胶质细胞与等基因对照具有显著的转录组相似性。相比之下，具有风险的PLCG2M28L小胶质细胞与PLCG2KO小胶质细胞有相似之处，在功能上TREM2表达降低，炎症反应减弱，增殖和细胞死亡增加。独特的是，PLCG2P522R小胶质细胞在脂多糖（LPS）刺激后细胞因子分泌增加，并被保护免于凋亡。这些发现表明PLCG2变体驱动不同的小胶质细胞转录组，影响小胶质细胞功能反应，可能有助于AD风险和保护。靶向plcg2介导的信号可能是调节神经炎症的一种强有力的治疗策略。研究了阿尔茨海默病保护和风险相关的磷脂酶C γ 2 （PLCG2）变异对诱导多能干细胞（iPSC）衍生的小胶质细胞转录组和功能的影响。PLCG2风险变异小胶质细胞表现出与PLCG2缺陷小胶质细胞相似的基础转录谱，但与同型对照和转录相似的PLCG2保护性变异小胶质细胞显著不同。PLCG2风险变异和PLCG2缺陷小胶质细胞显示髓样细胞2 （TREM2）上触发受体表达水平降低。保护性和风险相关PLCG2变异小胶质细胞的不同转录途径在功能上影响增殖、凋亡和免疫反应。保护性PLCG2小胶质细胞在暴露于脂多糖（LPS）时表现出对凋亡的恢复能力和细胞因子/趋化因子分泌的增加。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.