Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA ; Institute of Psychiatry, Department of Neuroscience, King's College London, DeCrespigny Park, London SE5 8AF, UK.
Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
Alzheimers Res Ther. 2013 Oct 23;5(5):49. doi: 10.1186/alzrt214. eCollection 2013.
Accumulation and aggregation of the microtubule-associated protein tau are a pathological hallmark of neurodegenerative disorders such as Alzheimer's disease (AD). In AD, tau becomes abnormally phosphorylated and forms inclusions throughout the brain, starting in the entorhinal cortex and progressively affecting additional brain regions as the disease progresses. Formation of these inclusions is thought to lead to synapse loss and cell death. Tau is also found in the cerebrospinal fluid (CSF), and elevated levels are a biomarker for AD. Until recently, it was thought that the presence of tau in the CSF was due to the passive release of aggregated tau from dead or dying tangle-bearing neurons. However, accumulating evidence from different AD model systems suggests that tau is actively secreted and transferred between synaptically connected neurons. Transgenic mouse lines with localized expression of aggregating human tau in the entorhinal cortex have demonstrated that, as these animals age, tau becomes mislocalized from axons to cell bodies and dendrites and that human tau-positive aggregates form first in the entorhinal cortex and later in downstream projection targets. Numerous in vitro and in vivo studies have provided insight into the mechanisms by which tau may be released and internalized by neurons and have started to provide insight into how tau pathology may spread in AD. In this review, we discuss the evidence for regulated tau release and its specific uptake by neurons. Furthermore, we identify possible therapeutic targets for preventing the propagation of tau pathology, as inhibition of tau transfer may restrict development of tau tangles in a small subset of neurons affected in early stages of AD and therefore prevent widespread neuron loss and cognitive dysfunction associated with later stages of the disease.
微管相关蛋白 tau 的积累和聚集是神经退行性疾病（如阿尔茨海默病（AD））的病理标志之一。在 AD 中，tau 异常磷酸化并在大脑中形成包含物，首先在海马回皮质中出现，并随着疾病的进展逐渐影响其他大脑区域。这些包含物的形成被认为会导致突触丧失和细胞死亡。tau 也存在于脑脊液（CSF）中，其水平升高是 AD 的生物标志物。直到最近，人们还认为 CSF 中 tau 的存在是由于聚集的 tau 从死亡或濒死的缠结神经元中被动释放所致。然而，来自不同 AD 模型系统的越来越多的证据表明，tau 是主动分泌的，并在突触连接的神经元之间转移。在海马回皮质中局部表达聚集性人 tau 的转基因小鼠系表明，随着这些动物年龄的增长，tau 从轴突错误定位到细胞体和树突，并且人 tau 阳性包含物首先在海马回皮质中形成，然后在下游投射靶标中形成。许多体外和体内研究提供了关于 tau 如何被神经元释放和内化的机制的见解，并开始提供关于 tau 病理学如何在 AD 中传播的见解。在这篇综述中，我们讨论了受调控的 tau 释放及其被神经元特异性摄取的证据。此外，我们确定了可能的治疗靶点，以防止 tau 病理学的传播，因为抑制 tau 转移可能会限制 AD 早期受影响的一小部分神经元中 tau 缠结的发展，并因此防止与疾病后期相关的广泛神经元丧失和认知功能障碍。
