1 Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (HW-LINE), Bristol, UK.
2 Centre for Synaptic Plasticity, Faculty of Health Sciences, University of Bristol, Bristol, UK.
Neuroscientist. 2017 Apr;23(2):137-151. doi: 10.1177/1073858416633439. Epub 2016 Jul 7.
Tauopathies encompass a broad range of neurodegenerative diseases featuring extensive neuronal death and cognitive decline. However, research over the past 30 years has failed to significantly advance our understanding of how tau causes dementia, limiting the design of rational therapeutics. It has become evident that we need to expand our understanding of tau in physiology, in order to delineate how tau may contribute to pathology. This review discusses recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterized localization to the synapse. Here, multiple streams of evidence support a critical role for synaptic tau in the regulation of synapse physiology. In particular, long-term depression, a form of synaptic weakening, is dependent on the presence of tau in hippocampal neurons. The regulation of tau by specific phosphorylation events downstream of GSK-3β activation appears to be integral to this signaling role. We also describe how the regulation of synapse physiology by tau and its phosphorylation may inform our understanding of tauopathies and comorbid diseases. This work should provide a platform for future tau biology research in addition to therapeutic design.
tau 病涵盖了广泛的神经退行性疾病，其特征是广泛的神经元死亡和认知能力下降。然而，过去 30 年的研究未能显著提高我们对 tau 如何导致痴呆的理解，限制了合理治疗方法的设计。很明显，我们需要扩大对 tau 在生理学中的理解，以便阐明 tau 如何有助于病理学。这篇综述讨论了最近的证据，这些证据揭示了 tau 功能的一个新方面，基于其以前未被描述的定位于突触。在这里，多股证据支持突触 tau 在调节突触生理学中的关键作用。特别是，长时程抑制，一种突触减弱的形式，依赖于海马神经元中 tau 的存在。由 GSK-3β 激活下游的特定磷酸化事件对 tau 的调节似乎是这种信号作用的组成部分。我们还描述了 tau 及其磷酸化对突触生理学的调节如何为我们理解 tau 病和共病提供信息。这项工作除了治疗设计外，还应该为未来的 tau 生物学研究提供一个平台。
