Department of Neuroscience, King's College London, Institute of Psychiatry , London , UK.
Front Neurol. 2013 Jul 1;4:83. doi: 10.3389/fneur.2013.00083. eCollection 2013.
Fibrillar deposits of highly phosphorylated tau are a key pathological feature of several neurodegenerative tauopathies including Alzheimer's disease (AD) and some frontotemporal dementias. Increasing evidence suggests that the presence of these end-stage neurofibrillary lesions do not cause neuronal loss, but rather that alterations to soluble tau proteins induce neurodegeneration. In particular, aberrant tau phosphorylation is acknowledged to be a key disease process, influencing tau structure, distribution, and function in neurons. Although typically described as a cytosolic protein that associates with microtubules and regulates axonal transport, several additional functions of tau have recently been demonstrated, including roles in DNA stabilization, and synaptic function. Most recently, studies examining the trans-synaptic spread of tau pathology in disease models have suggested a potential role for extracellular tau in cell signaling pathways intrinsic to neurodegeneration. Here we review the evidence showing that tau phosphorylation plays a key role in neurodegenerative tauopathies. We also comment on the tractability of altering phosphorylation-dependent tau functions for therapeutic intervention in AD and related disorders.
高度磷酸化的 tau 纤维沉积是包括阿尔茨海默病（AD）和一些额颞叶痴呆在内的几种神经退行性 tau 病的主要病理特征。越来越多的证据表明，这些终末期神经纤维缠结并不会导致神经元丢失，而是可溶性 tau 蛋白的改变诱导了神经退行性变。特别是，tau 的异常磷酸化被认为是一个关键的疾病过程，影响 tau 在神经元中的结构、分布和功能。尽管 tau 通常被描述为一种与微管结合并调节轴突运输的细胞质蛋白，但最近已经证明了 tau 的几个其他功能，包括在 DNA 稳定和突触功能中的作用。最近，研究检查了疾病模型中 tau 病理学的跨突触传播，表明细胞外 tau 在神经退行性变中固有细胞信号通路中可能发挥作用。在这里，我们回顾了 tau 磷酸化在神经退行性 tau 病中起关键作用的证据。我们还评论了改变依赖磷酸化的 tau 功能以治疗 AD 和相关疾病的可行性。
