Chen Yanting, Hong Tingting, Chen Feng, Sun Yuanhong, Wang Yan, Cui Lili
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States.
Front Aging Neurosci. 2021 Apr 8;13:631827. doi: 10.3389/fnagi.2021.631827. eCollection 2021.
As the main immune cells of the central nervous system (CNS), microglia regulates normal development, homeostasis and general brain physiology. These functions put microglia at the forefront of CNS repair and recovery. Uncontrolled activation of microglia is related to the course of neurodegenerative diseases such as Alzheimer's disease. It is clear that the classic pathologies of amyloid β (Aβ) and Tau are usually accompanied by the activation of microglia, and the activation of microglia also serves as an early event in the pathogenesis of AD. Therefore, during the occurrence and development of AD, the key susceptibility factors for AD-apolipoprotein E (APOE) genotype, sex and age-may further interact with microglia to exacerbate neurodegeneration. In this review, we discuss the role of microglia in the progression of AD related to the three risk factors for AD: APOE genotype, sex and aging. APOE-expressing microglia accumulates around Aβ plaques, and the presence of APOE4 may disrupt the phagocytosis of Aβ aggregates and aggravate neurodegeneration in Tau disease models. In addition, females have a high incidence of AD, and normal female microglia and estrogen have protective effects under normal conditions. However, under the influence of AD, female microglia seem to lose their protective effect and instead accelerate the course of AD. Aging, another major risk factor, may increase the sensitivity of microglia, leading to the exacerbation of microglial dysfunction in elderly AD. Obviously, in the role of microglia in AD, the three main risk factors of APOE, sex, and aging are not independent and have synergistic effects that contribute to the risk of AD. Moreover, new microglia can replace dysfunctional microglia after microglial depletion, which is a new promising strategy for AD treatment.
作为中枢神经系统（CNS）的主要免疫细胞，小胶质细胞调节正常发育、体内平衡和大脑整体生理功能。这些功能使小胶质细胞处于中枢神经系统修复和恢复的前沿。小胶质细胞的不受控制的激活与诸如阿尔茨海默病等神经退行性疾病的病程相关。显然，淀粉样β（Aβ）和Tau的经典病理学通常伴随着小胶质细胞的激活，并且小胶质细胞的激活也作为阿尔茨海默病发病机制中的早期事件。因此，在阿尔茨海默病的发生和发展过程中，阿尔茨海默病的关键易感因素——载脂蛋白E（APOE）基因型、性别和年龄——可能进一步与小胶质细胞相互作用，加剧神经退行性变。在本综述中，我们讨论小胶质细胞在与阿尔茨海默病的三个风险因素（APOE基因型、性别和衰老）相关的阿尔茨海默病进展中的作用。表达APOE的小胶质细胞在Aβ斑块周围积聚，并且APOE4的存在可能破坏Aβ聚集体的吞噬作用并加剧Tau病模型中的神经退行性变。此外，女性患阿尔茨海默病的发病率较高，正常的雌性小胶质细胞和雌激素在正常条件下具有保护作用。然而，在阿尔茨海默病的影响下，雌性小胶质细胞似乎失去了它们的保护作用，反而加速了阿尔茨海默病的病程。衰老，另一个主要风险因素，可能增加小胶质细胞的敏感性，导致老年阿尔茨海默病患者小胶质细胞功能障碍加剧。显然，在小胶质细胞在阿尔茨海默病中的作用方面，APOE、性别和衰老这三个主要风险因素并非相互独立，而是具有协同作用，促成了患阿尔茨海默病的风险。此外，新的小胶质细胞可以在小胶质细胞耗竭后替代功能失调的小胶质细胞，这是一种新的有前景的阿尔茨海默病治疗策略。
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