Molecular Neuropathology of Neurodegenerative Diseases, German Centre for Neurodegenerative Diseases (DZNE), 72072 Tübingen, Germany.
Department of Neuropathology, University of Tübingen, 72076 Tübingen, Germany.
Cells. 2023 May 23;12(11):1450. doi: 10.3390/cells12111450.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders often co-occurring in the same patient, a feature that suggests a common origin of the two diseases. Consistently, pathological inclusions of the same proteins as well as mutations in the same genes can be identified in both ALS/FTD. Although many studies have described several disrupted pathways within neurons, glial cells are also regarded as crucial pathogenetic contributors in ALS/FTD. Here, we focus our attention on astrocytes, a heterogenous population of glial cells that perform several functions for optimal central nervous system homeostasis. Firstly, we discuss how post-mortem material from ALS/FTD patients supports astrocyte dysfunction around three pillars: neuroinflammation, abnormal protein aggregation, and atrophy/degeneration. Furthermore, we summarize current attempts at monitoring astrocyte functions in living patients using either novel imaging strategies or soluble biomarkers. We then address how astrocyte pathology is recapitulated in animal and cellular models of ALS/FTD and how we used these models both to understand the molecular mechanisms driving glial dysfunction and as platforms for pre-clinical testing of therapeutics. Finally, we present the current clinical trials for ALS/FTD, restricting our discussion to treatments that modulate astrocyte functions, directly or indirectly.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是两种致命的神经退行性疾病，常同时发生在同一患者身上，这一特征表明这两种疾病可能具有共同的起源。事实上，在 ALS/FTD 患者中可以同时发现相同蛋白的病理性包涵体和相同基因的突变。尽管许多研究已经描述了神经元内的几个异常通路，但神经胶质细胞也被认为是 ALS/FTD 的重要致病因素。在这里，我们将注意力集中在星形胶质细胞上，星形胶质细胞是一种具有多种功能的神经胶质细胞，对中枢神经系统的稳态至关重要。首先，我们讨论了 ALS/FTD 患者的尸检材料如何围绕三个支柱支持星形胶质细胞功能障碍：神经炎症、异常蛋白聚集和萎缩/变性。此外，我们总结了目前使用新型成像策略或可溶性生物标志物在活体患者中监测星形胶质细胞功能的尝试。然后，我们研究了星形胶质细胞病理学在 ALS/FTD 的动物和细胞模型中的重现情况，以及我们如何利用这些模型来了解驱动神经胶质功能障碍的分子机制，并将其作为临床前治疗药物测试的平台。最后，我们介绍了目前针对 ALS/FTD 的临床试验，我们的讨论仅限于直接或间接调节星形胶质细胞功能的治疗方法。
