The Reynolds Family Spine Laboratory, Department of Neurological Surgery, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, United States.
Brain Res. 2021 May 1;1758:147291. doi: 10.1016/j.brainres.2021.147291. Epub 2021 Jan 28.
Classically, the loss of vulnerable neuronal populations in neurodegenerative diseases was considered to be the consequence of cell autonomous degeneration of neurons. However, progress in the understanding of glial function, the availability of improved animal models recapitulating the features of the human diseases, and the development of new approaches to derive glia and neurons from induced pluripotent stem cells obtained from patients, provided novel information that altered this view. Current evidence strongly supports the notion that non-cell autonomous mechanisms contribute to the demise of neurons in neurodegenerative disorders, and glia causally participate in the pathogenesis and progression of these diseases. In addition to microglia, astrocytes have emerged as key players in neurodegenerative diseases and will be the focus of the present review. Under the influence of pathological stimuli present in the microenvironment of the diseased CNS, astrocytes undergo morphological, transcriptional, and functional changes and become reactive. Reactive astrocytes are heterogeneous and exhibit neurotoxic (A1) or neuroprotective (A2) phenotypes. In recent years, single-cell or single-nucleus transcriptome analyses unraveled new, disease-specific phenotypes beyond A1/A2. These investigations highlighted the complexity of the astrocytic responses to CNS pathology. The present review will discuss the contribution of astrocytes to neurodegenerative diseases with particular emphasis on Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Some of the commonalties and differences in astrocyte-mediated mechanisms that possibly drive the pathogenesis or progression of the diseases will be summarized. The emerging view is that astrocytes are potential new targets for therapeutic interventions. A comprehensive understanding of astrocyte heterogeneity and disease-specific phenotypic complexity could facilitate the design of novel strategies to treat neurodegenerative disorders.
从经典观点来看，神经退行性疾病中易损神经元群体的丧失被认为是神经元自主退化的结果。然而，对神经胶质功能的理解的进展，能够重现人类疾病特征的改良动物模型的可用性，以及从患者获得的诱导多能干细胞中衍生神经胶质和神经元的新方法的发展，提供了改变这种观点的新信息。目前的证据强烈支持这样一种观点，即非细胞自主机制有助于神经退行性疾病中神经元的死亡，而神经胶质在这些疾病的发病机制和进展中起因果作用。除了小胶质细胞，星形胶质细胞已成为神经退行性疾病的关键参与者，将成为本综述的重点。在患病中枢神经系统微环境中存在的病理刺激的影响下，星形胶质细胞经历形态、转录和功能变化，并变得活跃。反应性星形胶质细胞是异质的，表现出神经毒性（A1）或神经保护（A2）表型。近年来，单细胞或单核转录组分析揭示了除 A1/A2 之外的新的、疾病特异性表型。这些研究强调了星形胶质细胞对中枢神经系统病理反应的复杂性。本综述将讨论星形胶质细胞对神经退行性疾病的贡献，特别强调阿尔茨海默病、帕金森病、肌萎缩侧索硬化症和额颞叶痴呆。将总结星形胶质细胞介导的机制在可能驱动疾病发病机制或进展方面的一些共同和差异。新兴观点认为，星形胶质细胞是治疗干预的潜在新靶点。全面了解星形胶质细胞的异质性和疾病特异性表型的复杂性，可以促进治疗神经退行性疾病的新策略的设计。
