中国科学院动物研究所胡宝洋小组揭示了在阿尔茨海默Aβ沉积小鼠模型中，小胶质细胞TMEM119结合淀粉样蛋白-β促进其清除。2025年5月14日出版的《免疫学》杂志发表了这项成果。

研究人员观察到淀粉样蛋白β (Aβ)诱导小胶质细胞中TMEM119表达减少，在5×FAD小鼠模型中TMEM119缺乏会增加AD的进展。TMEM119结合Aβ低聚物并招募低密度脂蛋白受体1，后者反过来降解TMEM119本身。TMEM119在小胶质细胞中的过表达增强了它们的吞噬活性，减轻了5xFAD小鼠的认知缺陷。研究人员发现小分子Kartogenin和SRI-011381可以增强TMEM119的表达，即使在疾病的中期，也能显著促进AD小鼠的Aβ清除和认知功能的改善。这些发现确定TMEM119是一个有希望的治疗AD的靶点。

据悉，阿尔茨海默病（AD）的进展涉及小胶质细胞激活的时间动力学。恢复或维持小胶质细胞的稳态已成为对抗阿尔茨海默病的一种有前途的治疗策略。跨膜蛋白119 （TMEM119）是小胶质细胞的稳态标志物，但在AD病理条件下尚未得到充分研究。

附：英文原文

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

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

Issue&Volume: 2025-05-14

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.

DOI: 10.1016/j.immuni.2025.04.018

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00181-5