源自 SH-SY5Y 的神经元：一种用于研究 TAU 分拣和神经元亚型特异性 TAU 易损性的人类神经元模型系统。

SH-SY5Y-derived neurons: a human neuronal model system for investigating TAU sorting and neuronal subtype-specific TAU vulnerability.

机构信息

Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 34, 50931 Cologne, Germany.

Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, 50931 Cologne, Germany.

出版信息

Rev Neurosci. 2021 Apr 19;33(1):1-15. doi: 10.1515/revneuro-2020-0152. Print 2022 Jan 27.

DOI:10.1515/revneuro-2020-0152

PMID:33866701

Abstract

The microtubule-associated protein (MAP) TAU is mainly sorted into the axon of healthy brain neurons. Somatodendritic missorting of TAU is a pathological hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Cause, consequence and (patho)physiological mechanisms of TAU sorting and missorting are understudied, in part also because of the lack of readily available human neuronal model systems. The human neuroblastoma cell line SH-SY5Y is widely used for studying TAU physiology and TAU-related pathology in AD and related tauopathies. SH-SY5Y cells can be differentiated into neuron-like cells (SH-SY5Y-derived neurons) using various substances. This review evaluates whether SH-SY5Y-derived neurons are a suitable model for (i) investigating intracellular TAU sorting in general, and (ii) with respect to neuron subtype-specific TAU vulnerability. (I) SH-SY5Y-derived neurons show pronounced axodendritic polarity, high levels of axonally localized TAU protein, expression of all six human brain isoforms and TAU phosphorylation similar to the human brain. As SH-SY5Y cells are highly proliferative and readily accessible for genetic engineering, stable transgene integration and leading-edge genome editing are feasible. (II) SH-SY5Y-derived neurons display features of subcortical neurons early affected in many tauopathies. This allows analyzing brain region-specific differences in TAU physiology, also in the context of differential vulnerability to TAU pathology. However, several limitations should be considered when using SH-SY5Y-derived neurons, e.g., the lack of clearly defined neuronal subtypes, or the difficulty of mimicking age-related tauopathy risk factors . In brief, this review discusses the suitability of SH-SY5Y-derived neurons for investigating TAU (mis)sorting mechanisms and neuron-specific TAU vulnerability in disease paradigms.

摘要

微管相关蛋白（MAP）TAU 主要被分拣到健康大脑神经元的轴突中。TAU 的树突-胞体分拣错误是包括阿尔茨海默病（AD）在内的许多神经退行性疾病的病理性标志。TAU 分拣和分拣错误的原因、后果和（病理）生理机制研究不足，部分原因是缺乏现成的人类神经元模型系统。人神经母细胞瘤细胞系 SH-SY5Y 广泛用于研究 AD 和相关 tau 病中 TAU 的生理学和 TAU 相关病理学。可以使用各种物质将 SH-SY5Y 细胞分化为类神经元细胞（SH-SY5Y 衍生神经元）。本综述评估了 SH-SY5Y 衍生神经元是否适合（i）研究一般的细胞内 TAU 分拣，以及（ii）针对神经元亚型特异性 TAU 易感性。（i）SH-SY5Y 衍生神经元表现出明显的轴突树突极性、高水平的轴突 TAU 蛋白、所有六种人类脑同工型的表达以及类似于人脑的 TAU 磷酸化。由于 SH-SY5Y 细胞具有高度增殖性，并且易于进行基因工程，因此可以进行稳定的转基因整合和前沿基因组编辑。（ii）SH-SY5Y 衍生神经元表现出许多 tau 病中早期受影响的皮质下神经元的特征。这允许分析脑区特异性 TAU 生理学差异，也可以在不同的 TAU 病理学易感性的背景下进行分析。然而，在使用 SH-SY5Y 衍生神经元时应考虑到几个局限性，例如缺乏明确的神经元亚型，或者难以模拟与年龄相关的 tau 病风险因素。总之，本综述讨论了 SH-SY5Y 衍生神经元在疾病模型中研究 TAU（错误）分拣机制和神经元特异性 TAU 易感性的适宜性。