G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.

IF 15 1区医学 Q1 NEUROSCIENCES

Neuron Pub Date : 2025-07-23 DOI:10.1016/j.neuron.2025.06.020

Beika Zhu, Andi Wangzhou, Diankun Yu, Tao Li, Rachael Schmidt, Stacy L De Florencio, Lauren Chao, Alicia L Thurber, Minqi Zhou, Zeina Msheik, Yonatan Perez, Lea T Grinberg, Salvatore Spina, Richard M Ransohoff, Arnold R Kriegstein, William W Seeley, Tomasz Nowakowski, Xianhua Piao

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引用次数: 0

Abstract

Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms enabling protective microglial responses remain elusive. Here, we investigate the role of microglial ADGRG1, an adhesion G-protein-coupled receptor (aGPCR) specifically expressed in yolk-sac-derived microglia, in AD pathology using the 5xFAD mouse model. Transcriptomic analyses reveal that ADGRG1 activates the transcription factor MYC, leading to upregulation of genes involved in homeostasis, phagocytosis, and lysosomal functions, thereby promoting a protective microglial state. We demonstrate that deletion of Adgrg1 in microglia impairs MYC activation, resulting in increased amyloid-beta deposition, exacerbated neuronal loss, and cognitive deficits. Functional assays in mouse models and human embryonic stem cell-derived microglia confirm that ADGRG1 is required for Aβ phagocytosis. These findings uncover a GPCR-mediated pathway that drives a protective microglial state via MYC activation, suggesting potential therapeutic strategies to alleviate AD progression by enhancing microglial functional competence.

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g蛋白偶联受体ADGRG1通过MYC激活驱动阿尔茨海默病的保护性小胶质细胞状态。

阿尔茨海默病（AD）的种系遗传结构表明疾病易感性和结果的小胶质机制。然而，使保护性小胶质细胞反应的机制仍然难以捉摸。在这里，我们使用5xFAD小鼠模型研究了小胶质细胞ADGRG1（一种在卵黄囊源性小胶质细胞中特异性表达的粘附g蛋白偶联受体（aGPCR））在AD病理中的作用。转录组学分析显示，ADGRG1激活转录因子MYC，导致参与稳态、吞噬和溶酶体功能的基因上调，从而促进保护性小胶质细胞状态。我们证明，小胶质细胞中Adgrg1的缺失会损害MYC的激活，导致淀粉样蛋白沉积增加，神经元损失加剧和认知缺陷。小鼠模型和人胚胎干细胞衍生小胶质细胞的功能分析证实，ADGRG1是Aβ吞噬所必需的。这些发现揭示了gpcr介导的途径，通过MYC激活驱动保护性小胶质细胞状态，提示通过增强小胶质细胞功能能力来缓解AD进展的潜在治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuron 医学-神经科学

CiteScore

24.50

自引率

3.10%

发文量

382

审稿时长

1 months

期刊介绍： Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.