Tau is a microtubule-binding protein expressed in neurons, and the equal ratios between 4-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 recapitulate tau isoforms in health and disease will provide a platform for elucidating pathogenic processes involving tau pathology. We carried out extensive characterizations of tau isoforms expressed in human neurons derived by microRNA-induced neuronal reprogramming of adult fibroblasts. Transcript and protein analyses showed that miR neurons expressed all six isoforms with the 3R:4R isoform ratio equivalent to that detected in human adult brains. Also, miR neurons derived from familial tauopathy patients with a 3R:4R ratio altering mutation showed increased 4R tau and the formation of insoluble tau with seeding activity. Our results collectively demonstrate the utility of miRNA-induced neuronal reprogramming to recapitulate endogenous tau regulation comparable with the adult brain in health and disease.

Tau 是一种在神经元中表达的微管结合蛋白，在正常成人脑功能中维持 4 次重复 (4R) 和 3 次重复 (3R) 亚型之间的相等比例。3R:4R 比例失调会导致 tau 病，而在健康和疾病中重现 tau 亚型的人类神经元将为阐明涉及 tau 病理学的致病过程提供一个平台。我们对由 microRNA 诱导的成体成纤维细胞神经元重编程衍生的人类神经元中表达的 tau 亚型进行了广泛的表征。转录本和蛋白质分析表明，miR 神经元表达所有六种亚型，其中 3R:4R 亚型比例与在成人大脑中检测到的比例相当。此外，来自具有 3R:4R 比率改变突变的家族性 tau 病患者的 miR 神经元显示出 4R tau 增加，并形成具有播种活性的不溶性 tau。我们的结果共同证明了 miRNA 诱导的神经元重编程可重现内源性 tau 调节，与健康和疾病中的成人大脑相当。