PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD, emphasizing the urgent need for a comprehensive understanding of cell-specific pathology. Astrocytes, principal homeostatic cells of the central nervous system, are key players in the pathogenesis of neurodegenerative diseases, including AD. Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways. Tumor-derived and immortalized astrocytic cell lines, alongside the emerging technology of adult induced pluripotent stem cells, are widely used to study cellular dysfunction in AD. Surprisingly, no stable cell lines were available from genetic mouse AD models. Recently, we established immortalized hippocampal astroglial cell lines from amyloid-β precursor protein/presenilin-1/Tau triple-transgenic (3xTg)-AD mice (denominated as wild type (WT)- and 3Tg-iAstro cells) using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection, thereby maintaining natural heterogeneity of primary cultures. Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling, mitochondrial dysfunctions, disproteostasis, altered homeostatic and signaling support to neurons, and blood-brain barrier models. Here we provide a comparative overview of the most used models to study astrocytes in vitro, such as primary culture, tumor-derived cell lines, immortalized astroglial cell lines, and induced pluripotent stem cell-derived astrocytes. We conclude that immortalized WT- and 3Tg-iAstro cells provide a non-competitive but complementary, low-cost, easy-to-handle, and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery.
摘要：
阿尔茨海默病(AD)的病因复杂,持久的发病机制，和细胞类型特异性改变。目前,没有治愈AD的方法,强调迫切需要全面了解细胞特异性病理学。星形胶质细胞,中枢神经系统的主要稳态细胞，是神经退行性疾病发病机制的关键参与者，包括AD。细胞模型极大地促进了细胞特异性病理改变的研究以及分子机制和途径的解剖。肿瘤来源的和永生化的星形细胞细胞系，随着成人诱导多能干细胞的新兴技术，广泛用于研究AD中的细胞功能障碍。令人惊讶的是,从遗传小鼠AD模型中没有稳定的细胞系。最近,我们使用逆转录病毒介导的猿猴病毒40大T抗原的转导，从淀粉样β前体蛋白/早老素-1/Tau三转基因（3xTg）-AD小鼠（命名为野生型（WT）-和3Tg-iAstro细胞）中建立了永生化的海马星形胶质细胞系。从而保持原始文化的自然异质性。几个小组已经成功地将3Tg-iAstro细胞用于单细胞和组学方法来研究星形细胞AD相关的钙信号改变。线粒体功能障碍,disproproteostasis,改变了对神经元的稳态和信号支持，和血脑屏障模型。在这里，我们提供了最常用的体外研究星形胶质细胞模型的比较概述，比如初级文化，肿瘤来源的细胞系，永生化星形胶质细胞系，和诱导多能干细胞来源的星形胶质细胞。我们得出结论，永生化的WT-和3Tg-iAstro细胞提供了一种非竞争性但互补的细胞，低成本,易于处理，以及用于解剖星形胶质细胞特异性AD相关改变和临床前药物发现的通用细胞模型。
