《生命科学》 2026, 38(7): 1231-1240

线粒体-内质网串扰在阿尔茨海默病小胶质细胞衰老中的作用

潘 佳¹ , 刘传国^2,* , 刘慧敏^3,*

¹山东中医药大学中医学院，济南 250355 ²山东中医药大学实验中心，济南 250355 ³山东中医药大学医学院，济南 250355

摘　要：

阿尔茨海默病（Alzheimer′s disease，AD）作为一种神经退行性疾病，衰老是其主要危险因素。细胞衰老是 一种与促炎症分泌体相关的永久性增殖停滞状态，被认为是导致衰老和衰老相关疾病（包括AD）的重要原因。小胶 质细胞（microglia，MG）作为大脑常驻免疫细胞，其衰老是AD的重要致病因素，并且已经在AD 患者和 AD 动物模型 的大脑中检测到衰老的MG。通过基因或药物去除衰老细胞可改善β-淀粉样蛋白（Aβ）肽和tau蛋白诱导的神经病理 变化，并改善AD模型小鼠的学习记忆，这表明细胞衰老在AD病理生理学中起着关键作用。影响MG衰老的因素众 多，主要包括DNA损伤、端粒缩短、氧化应激、炎症、线粒体功能障碍及代谢紊乱等。最新研究发现，线粒体-内质网 之间的信号串扰可能也是导致MG衰老的重要因素之一。线粒体与内质网密切接触的部位被称为线粒体相关膜 （mitochondria-associated membrane，MAM）或线粒体-内质网接触位点（mitochondria-endoplasmic reticulum contact site，MERCS）。MAM作为一种动态结构，参与脂质生物合成和运输、钙稳态、活性氧产生等过程，在细胞衰老过程中 起着重要作用。本文总结了这一领域的最新研究进展，并讨论了线粒体-内质网串扰导致MG衰老可能是AD的潜在 治疗靶点。

通讯作者：刘传国 , Email:60011973@sdutcm.edu.cn 刘慧敏 , Email:liuhm3009@163.com

The role of mitochondrial endoplasmic reticulum crosstalk in microglial senescence in Alzheimer′s disease

PAN Jia¹ , LIU Chuan-Guo^2,* , LIU Hui-Min^3,*

¹College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China ²Experimental Center of Shandong University of Traditional Chinese Medicine, Jinan 250355, China ³College of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China

Abstract:

Alzheimer′s disease (AD) is a neurodegenerative disease, and aging is its primary risk factor. Cellular senescence is a permanent state of proliferation arrest associated with pro-inflammatory cytokines, and it is regarded as a significant cause of aging and age-related diseases, including AD. Microglia (MG) are resident immune cells in the brain, and their aging is a crucial pathogenic factor in AD. Senescent MG have been detected in the brains of AD patients and animal models. Removing senescent cells via genetic or pharmacological approaches can alleviate the neuropathological changes induced by β-amyloid (Aβ) peptide and tau protein, and improve the learning and memory abilities of AD model mice, indicating that cellular senescence plays a key role in AD pathophysiology. There are numerous factors that influence the senescence of MG, primarily including DNA damage, telomere shortening, oxidative stress, inflammation, mitochondrial dysfunction, and metabolic disorders. The latest research has discovered that signal crosstalk between mitochondria and endoplasmic reticulum (ER) may also be one of the important factors contributing to MG senescence. There is mutual crosstalk between mitochondria and ER, and the site of close contact is called the mitochondria-associated membrane (MAM) or mitochondria- ER contact site (MERCS). As a dynamic structure, MAM is involved in processes such as lipid biosynthesis and transport, calcium homeostasis, and reactive oxygen species production. Meanwhile, it is a key region that regulates processes including mitochondrial function, cellular calcium homeostasis, lipid metabolism, oxidative stress, and inflammatory signaling pathways, and is closely related to endoplasmic reticulum stress, and plays an important role in cellular senescence. In this review, we summarize the latest research progress in this field, and consolidate evidence indicating that the molecular mechanism of mitochondria-ER crosstalk drives MG senescence. In the end, we propose a novel therapeutic direction for AD caused by senescence based on targeting mitochondria-ER crosstalk to inhibit MG senescence.

Communication Author：LIU Chuan-Guo , Email:60011973@sdutcm.edu.cn LIU Hui-Min , Email:liuhm3009@163.com