美国圣路易斯华盛顿大学Andrew S. Yoo、英国伦敦大学学院Karen E. Duff等研究人员合作发现，直接重编程的人类神经元中可实现内源性4R tau表达的重现和不溶性tau的形成。这一研究成果于2022年6月2日发表在国际学术期刊《细胞—干细胞》上。

研究人员表示，tau是一种在神经元中表达的微管结合蛋白，4重复（4R）和3重复（3R）异构体之间的相等比例在正常的成人大脑功能中保持。3R:4R的比例失调会导致tau病理，而再现tau异构体在健康和疾病中的人类神经元将为阐明涉及tau病理的致病过程提供一个平台。

研究人员对通过microRNA诱导的成人成纤维细胞的神经元重编程所产生的人类神经元中表达的tau异构体进行了广泛的特征分析。转录本和蛋白质分析显示，miR神经元表达所有六种异构体，3R：4R的异构体比例与在人类成年大脑中检测到的相当。此外，来自具有3R:4R比例改变突变的家族性tau病理患者的miR神经元显示出4R tau的增加和具有播种活性的不溶性tau形成。这些结果共同证明了miRNA诱导的神经元重编程在健康和疾病中再现与成人大脑相当的内源性tau调节的效用。

附：英文原文

Title: Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons

Author: Lucia S. Capano, Chihiro Sato, Elena Ficulle, Anan Yu, Kanta Horie, Ji-Sun Kwon, Kyle F. Burbach, Nicolas R. Barthélemy, Susan G. Fox, Celeste M. Karch, Randall J. Bateman, Henry Houlden, Richard I. Morimoto, David M. Holtzman, Karen E. Duff, Andrew S. Yoo

Issue&Volume: 2022/06/02

Abstract: Tau is a microtubule-binding protein expressed in neurons, and the equal ratios between4-repeat (4R) and 3-repeat (3R) isoforms are maintained in normal adult brain function.Dysregulation of 3R:4R ratio causes tauopathy, and human neurons that recapitulatetau isoforms in health and disease will provide a platform for elucidating pathogenicprocesses involving tau pathology. We carried out extensive characterizations of tauisoforms expressed in human neurons derived by microRNA-induced neuronal reprogrammingof adult fibroblasts. Transcript and protein analyses showed that miR neurons expressedall six isoforms with the 3R:4R isoform ratio equivalent to that detected in humanadult brains. Also, miR neurons derived from familial tauopathy patients with a 3R:4Rratio altering mutation showed increased 4R tau and the formation of insoluble tauwith seeding activity. Our results collectively demonstrate the utility of miRNA-inducedneuronal reprogramming to recapitulate endogenous tau regulation comparable with theadult brain in health and disease.

DOI: 10.1016/j.stem.2022.04.018

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00200-4