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 vitro. 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.

中文翻译：

---

SH-SY5Y 衍生神经元：用于研究 TAU 分类和神经元亚型特异性 TAU 脆弱性的人类神经元模型系统

微管相关蛋白 (MAP) TAU 主要分类到健康脑神经元的轴突中。TAU 的 Somatodendritic missorting 是许多神经退行性疾病的病理标志，包括阿尔茨海默病 (AD)。TAU 分类和错误分类的原因、后果和（病理）生理机制尚未得到充分研究，部分原因还在于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 病变中的 TAU 生理学和 TAU 相关病理学。SH-SY5Y细胞可以使用各种物质分化成神经元样细胞（SH-SY5Y衍生的神经元）。本综述评估了 SH-SY5Y 衍生的神经元是否适合 (i) 研究细胞内 TAU 分类，(ii) 关于神经元亚型特异性 TAU 脆弱性。(I) SH-SY5Y 衍生的神经元表现出明显的轴突极性、高水平的轴突定位 TAU 蛋白、所有六种人脑同种型的表达和与人脑相似的 TAU 磷酸化。由于 SH-SY5Y 细胞具有高度增殖性并且易于用于基因工程，因此稳定的转基因整合和前沿基因组编辑是可行的。(II) SH-SY5Y 衍生的神经元表现出在许多 tau 病变中早期受影响的皮层下神经元的特征。这允许分析 TAU 生理学中大脑区域特定的差异，也在对 TAU 病理学的不同脆弱性的背景下。然而，在使用 SH-SY5Y 衍生的神经元时应考虑一些限制，例如，缺乏明确定义的神经元亚型，体外. 简而言之，这篇综述讨论了 SH-SY5Y 衍生的神经元对研究 TAU（错误）分类机制和疾病范式中神经元特异性 TAU 脆弱性的适用性。