Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
Lab for Translational Research of Neurodegenerative Diseases, Shanghai Institute for Advanced Immunochemical Studies (SIAIS), Shanghai Tech University, 201210, Shanghai, China.
Signal Transduct Target Ther. 2023 Sep 22;8(1):359. doi: 10.1038/s41392-023-01588-0.
Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.
小胶质细胞激活可见于各种神经退行性疾病中。单细胞技术的最新进展表明，这些反应性小胶质细胞具有高度的时空异质性。一些特定状态的小胶质细胞与病理特征相关，并与特定功能相关。小胶质细胞通过吞噬和清除病理蛋白聚集体发挥保护作用，但由于过度摄取蛋白聚集体，也会导致小胶质细胞吞噬能力受损、神经炎症，最终导致神经退行性变。此外，外周免疫细胞浸润使小胶质细胞形成促炎表型，并加速疾病进展。小胶质细胞还充当可传播蛋白聚集体的移动载体。小胶质细胞释放的细胞外囊泡和自噬受损都有助于病理进展和神经退行性变。因此，增强小胶质细胞的吞噬作用、减少小胶质细胞介导的神经炎症、抑制小胶质细胞外泌体的合成和分泌、促进小胶质细胞向保护表型转化被认为是神经退行性疾病治疗的有前途的策略。在这里，我们全面综述了小胶质细胞的生物学特性及其在神经退行性疾病中的作用，包括阿尔茨海默病、帕金森病、多系统萎缩、肌萎缩侧索硬化症、额颞叶痴呆、进行性核上性麻痹、皮质基底节变性、路易体痴呆和亨廷顿病。我们还总结了具有细胞实验、动物研究和临床试验的临床前和临床证据的针对神经退行性疾病的小胶质细胞靶向干预和治疗方法。
