成熟的后有丢失细胞周期激活导致细胞凋亡而不是细胞转化的能力，因此后期有丢失细胞需要持续活跃的控制来维持终末分化。在阿尔茨海默病（AD）和相关tau病理中，有证据表明病理性tau的形态通过神经元细胞周期再入驱动神经退行性病变。已经鉴定出了多个相互关联的机制，将tau与细胞周期激活联系起来，包括但不限于tau引起的肌动蛋白细胞骨架过度稳定化、随之发生的核结构变化以及异染色质介导的基因沉默受损。结直肠癌易激发的途径和发育相关途径在tau病理的人类和细胞模型中上调，并且在各种癌症和祖细胞/干细胞中存在许多tau诱导的细胞表型。本综述研究揭示了tau病理、癌症和发育之间的机械性相似性，并重点强调了tau在癌症和发育脑中的作用。基于这些研究，我提出了一个模型，描述了病理性tau突变了维持终末神经元分化的程序，导致细胞周期再入和随之发生的神经元死亡。该框架将tau病理视为涉及重大有害扰乱神经元身份的情况。版权 © 2023 作者。由Elsevier Ltd.出版。版权所有。

Postmitotic neurons require persistently active controls to maintain terminal differentiation. Unlike dividing cells, aberrant cell cycle activation in mature neurons causes apoptosis rather than transformation. In Alzheimer's disease (AD) and related tauopathies, evidence suggests that pathogenic forms of tau drive neurodegeneration via neuronal cell cycle re-entry. Multiple interconnected mechanisms linking tau to cell cycle activation have been identified, including, but not limited to, tau-induced overstabilization of the actin cytoskeleton, consequent changes to nuclear architecture, and disruption of heterochromatin-mediated gene silencing. Cancer- and development-associated pathways are upregulated in human and cellular models of tauopathy, and many tau-induced cellular phenotypes are also present in various cancers and progenitor/stem cells. In this review, I delve into mechanistic parallels between tauopathies, cancer, and development, and highlight the role of tau in cancer and in the developing brain. Based on these studies, I put forth a model by which pathogenic forms of tau disrupt the program that maintains terminal neuronal differentiation, driving cell cycle re-entry and consequent neuronal death. This framework presents tauopathies as conditions involving the profound toxic disruption of neuronal identity.Copyright © 2023 The Author. Published by Elsevier Ltd.. All rights reserved.