Contribution of astrocytes to neuropathology of neurodegenerative diseases
Contribution of astrocytes to neuropathology of neurodegenerative diseases
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DOI：
10.1016/j.brainres.2021.147291
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发表时间：
2021-03-06
期刊：
影响因子：
2.9
通讯作者：
Elkabes, Stella
中科院分区：
文献类型：
--
作者：
Acioglu, Cigdem;Li, Lun;Elkabes, Stella
传统上，神经退行性疾病中脆弱神经元群体的丧失被认为是神经元的细胞自主变性的结果。然而，在理解神经胶质功能方面的进展，改进的动物模型重现人类疾病特征的可用性，以及从患者获得的诱导多能干细胞中获得神经胶质和神经元的新方法的开发，提供了改变这种观点的新信息。目前的证据有力地支持了这样的观点，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，并且胶质细胞因果地参与这些疾病的发病机制和进展。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球员，将是本审查的重点。在存在于患病CNS的微环境中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反应性。反应性星形胶质细胞是异质的，并表现出神经毒性（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A1/A2以外的新的疾病特异性表型。这些调查突出了复杂的星形胶质细胞反应CNS pathology.The本审查将讨论星形胶质细胞的神经退行性疾病的贡献，特别强调阿尔茨海默氏病，帕金森氏病，肌萎缩侧索硬化症和额颞叶痴呆。一些共同点和差异，星形胶质细胞介导的机制，可能驱动的发病机制或疾病的进展将进行总结。新出现的观点是星形胶质细胞是治疗干预的潜在新靶点。对星形胶质细胞异质性和疾病特异性表型复杂性的全面了解可以促进治疗神经退行性疾病的新策略的设计。
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.