Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
Mol Neurodegener. 2009 Mar 11;4:13. doi: 10.1186/1750-1326-4-13.
Since the identification of tau as the main component of neurofibrillary tangles in Alzheimer's disease and related tauopathies, and the discovery that mutations in the tau gene cause frontotemporal dementia, much effort has been directed towards determining how the aggregation of tau into fibrillar inclusions causes neuronal death. As evidence emerges that tau-mediated neuronal death can occur even in the absence of tangle formation, a growing number of studies are focusing on understanding how abnormalities in tau (e.g. aberrant phosphorylation, glycosylation or truncation) confer toxicity. Though data obtained from experimental models of tauopathies strongly support the involvement of pathologically modified tau and tau aggregates in neurodegeneration, the exact neurotoxic species remain unclear, as do the mechanism(s) by which they cause neuronal death. Nonetheless, it is believed that tau-mediated neurodegeneration is likely to result from a combination of toxic gains of function as well as from the loss of normal tau function. To truly appreciate the detrimental consequences of aberrant tau function, a better understanding of all functions carried out by tau, including but not limited to the role of tau in microtubule assembly and stabilization, is required. This review will summarize what is currently known regarding the involvement of tau in the initiation and development of neurodegeneration in tauopathies, and will also highlight some of the remaining questions in need of further investigation.
自 tau 被确定为阿尔茨海默病和相关 tau 病神经纤维缠结的主要成分，以及发现 tau 基因突变导致额颞叶痴呆以来，人们已经做出了很多努力来确定 tau 如何聚集形成纤维内包涵体导致神经元死亡。随着越来越多的证据表明，即使没有缠结形成，tau 介导的神经元死亡也可能发生，越来越多的研究开始关注了解 tau 的异常（例如异常磷酸化、糖基化或截断）如何产生毒性。尽管来自 tau 病实验模型的数据强烈支持病理性修饰的 tau 和 tau 聚集物参与神经退行性变，但确切的神经毒性物质仍不清楚，它们导致神经元死亡的机制也不清楚。尽管如此，人们相信 tau 介导的神经退行性变可能是病理性 tau 功能获得和正常 tau 功能丧失的综合结果。为了真正了解异常 tau 功能的有害后果，需要更好地了解 tau 执行的所有功能，包括但不限于 tau 在微管组装和稳定中的作用。这篇综述将总结 tau 在 tau 病神经退行性变的发生和发展中的作用的最新认识，并强调一些仍需要进一步研究的问题。
