Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Neurobiol Dis. 2012 Dec;48(3):356-66. doi: 10.1016/j.nbd.2012.05.021. Epub 2012 Jun 2.
The microtubule-associated protein tau plays a critical role in the pathogenesis of Alzheimer's disease and several related disorders. In the disease tau aggregates into paired helical and straight filaments, which can form higher order neurofibrillary tangles in neurons and this pathology is associated with progressive neuronal loss and cognitive decline. Tau is a cytoplasmic protein and is thought to be released only from degenerating cells. In contrast, here we provide evidence that tau is constitutively secreted at a low level. We directly show tau release in cell culture model systems. In inducible transfected cell lines we observe that a small proportion of full-length tau is released from intact cells in a time dependent manner. We show that this tau is released by an unconventional secretion process, as the release is temperature dependent but not blocked by inhibitors of the conventional secretory pathway. We characterize the released tau as full length, not vesicle associated and containing Phospho-Tau (181P) proportional to its intracellular concentration. We demonstrate that tau secretion and its suppression by low temperature also occurs in human neurons differentiated from induced pluripotent stem cells. The constitutive tau secretion that we propose provides the most parsimonious explanation for the observed presence of tau in the CSF of healthy animals and human beings. If previously postulated pathogenic extracellular tau intermediates are released by this route, low level constitutive tau secretion could play a role in the spread of tau pathology in Alzheimer's disease and other human tauopathies.
微管相关蛋白 tau 在阿尔茨海默病和几种相关疾病的发病机制中起着关键作用。在该疾病中，tau 聚集成成对的螺旋和直丝，可在神经元中形成更高阶的神经原纤维缠结，这种病理学与进行性神经元丧失和认知能力下降有关。tau 是一种细胞质蛋白，被认为仅从退化的细胞中释放。相比之下，在这里我们提供了 tau 持续低水平分泌的证据。我们直接在细胞培养模型系统中显示 tau 的释放。在可诱导的转染细胞系中，我们观察到一小部分全长 tau 以时间依赖性方式从完整细胞中释放出来。我们表明这种 tau 是通过非典型分泌过程释放的，因为释放依赖于温度，但不受常规分泌途径抑制剂的阻断。我们将释放的 tau 描述为全长，与囊泡无关，并且含有与其细胞内浓度成比例的磷酸化 tau（181P）。我们证明tau 分泌及其通过低温抑制也发生在诱导多能干细胞分化的人类神经元中。我们提出的持续 tau 分泌为观察到健康动物和人类 CSF 中存在 tau 提供了最合理的解释。如果以前假设的致病性细胞外 tau 中间体通过这种途径释放，那么低水平的持续 tau 分泌可能在阿尔茨海默病和其他人类 tau 病中的 tau 病理学传播中发挥作用。
