在阿尔茨海默病的Aβ沉积小鼠模型中，小胶质细胞的跨膜蛋白119（TMEM119）与β淀粉样蛋白（amyloid-β）结合，以促进其清除。

Microglial TMEM119 binds to amyloid-β to promote its clearance in an Aβ-depositing mouse model of Alzheimer's disease.

作者信息

Liu Jing, Wang Zhimeng, Liang Wenwen, Zhang Zhenhao, Deng Yusen, Chen Xiaowei, Hou Zongren, Xie Yuanzhi, Wang Qi, Li Yuan, Bai Chaobo, Li Da, Mo Fan, Wang Huinan, Wang Dongmei, Yuan Junliang, Wang Yukai, Teng Zhao-Qian, Hu Baoyang

机构信息

Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

School of Pharmaceutical Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, Beijing 100191, China.

出版信息

Immunity. 2025 Jul 8;58(7):1830-1846.e7. doi: 10.1016/j.immuni.2025.04.018. Epub 2025 May 14.

DOI:10.1016/j.immuni.2025.04.018

PMID:40373772

Abstract

The progression of Alzheimer's disease (AD) involves temporal dynamics of microglial activation. Restoring or maintaining microglial homeostasis has emerged as a promising therapeutic strategy to combat AD. Transmembrane protein 119 (TMEM119) is a homeostatic marker of microglia but has not been fully studied under AD pathological conditions. Here, we observed that amyloid-beta (Aβ) induced a decrease in TMEM119 expression in microglia, and TMEM119 deficiency increased AD progression in the 5×FAD mouse model. TMEM119 bound to Aβ oligomers and recruited low-density lipoprotein receptor 1, which in turn degraded TMEM119 itself. Overexpression of TMEM119 in microglia enhanced their phagocytic activity and alleviated cognitive deficits in 5xFAD mice. Administration of the small molecules Kartogenin and SRI-011381, which we found enhanced TMEM119 expression, substantially promoted Aβ clearance and improved cognitive function in AD mice, even during the mid-stage of the disease. These findings identify TMEM119 as a promising therapeutic target for AD.

摘要

阿尔茨海默病（AD）的进展涉及小胶质细胞激活的时间动态变化。恢复或维持小胶质细胞的稳态已成为对抗AD的一种有前景的治疗策略。跨膜蛋白119（TMEM119）是小胶质细胞的一种稳态标志物，但在AD病理条件下尚未得到充分研究。在此，我们观察到淀粉样β蛋白（Aβ）诱导小胶质细胞中TMEM119表达降低，并且在5×FAD小鼠模型中，TMEM119缺乏会加速AD进展。TMEM119与Aβ寡聚体结合并募集低密度脂蛋白受体1，进而降解TMEM119自身。在小胶质细胞中过表达TMEM119可增强其吞噬活性，并减轻5xFAD小鼠的认知缺陷。我们发现小分子卡托金和SRI - 011381可增强TMEM119表达，即使在疾病中期，给予这些小分子也能显著促进AD小鼠的Aβ清除并改善其认知功能。这些发现表明TMEM119是AD一个有前景的治疗靶点。