Tang Zhi, Ioja Eniko, Bereczki Erika, Hultenby Kjell, Li Chunxia, Guan Zhizhong, Winblad Bengt, Pei Jin-Jing
Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden; Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
Karolinska Institutet, NVS Department, Centrum for Alzheimer Research, Division for Neurogeriatrics, Novum, SE 14186 Stockholm, Sweden.
Biochim Biophys Acta. 2015 Jul;1853(7):1646-57. doi: 10.1016/j.bbamcr.2015.03.003. Epub 2015 Mar 17.
Abnormally hyperphosphorylated tau aggregates form paired helical filaments (PHFs) in neurofibrillary tangles, a key hallmark of Alzheimer's disease (AD) and other tauopathies. The cerebrospinal fluid (CSF) levels of soluble total tau and phospho-tau from clinically diagnosed AD patients are significantly higher compared with controls. Data from both in vitro and in vivo AD models have implied that an aberrant increase of mammalian target of rapamycin (mTor) signaling may be a causative factor for the formation of abnormally hyperphosphorylated tau. In the present study, we showed that in post-mortem human AD brain, tau was localized within different organelles (autophagic vacuoles, endoplasmic reticulum, Golgi complexes, and mitochondria). In human SH-SY5Y neuroblastoma cells stably carrying different genetic variants of mTor, we found a common link between the synthesis and distribution of intracellular tau. mTor overexpression or the lack of its expression was responsible for the altered balance of phosphorylated (p-)/-non phosphorylated (Np-) tau in the cytoplasm and different cellular compartments, which might facilitate tau deposition. Up-regulated mTor activity resulted in a significant increase in the amount of cytosolic tau as well as its re-localization to exocytotic vesicles that were not associated with exosomes. These results have implicated that mTor is involved in regulating tau distribution in subcellular organelles and in the initiation of tau secretion from cells to extracellular space.
异常过度磷酸化的tau聚集体在神经原纤维缠结中形成双螺旋丝（PHF），这是阿尔茨海默病（AD）和其他tau蛋白病的一个关键标志。与对照组相比，临床诊断为AD的患者脑脊液（CSF）中可溶性总tau和磷酸化tau的水平显著更高。来自体外和体内AD模型的数据都表明，雷帕霉素哺乳动物靶标（mTor）信号异常增加可能是异常过度磷酸化tau形成的一个致病因素。在本研究中，我们表明在死后的人类AD大脑中，tau定位于不同的细胞器（自噬泡、内质网、高尔基体和线粒体）内。在稳定携带mTor不同基因变体的人类SH-SY5Y神经母细胞瘤细胞中，我们发现细胞内tau的合成与分布之间存在共同联系。mTor的过表达或其表达缺失导致细胞质和不同细胞区室中磷酸化（p-）/非磷酸化（Np-）tau的平衡改变，这可能促进tau沉积。mTor活性上调导致胞质tau量显著增加，以及其重新定位于与外泌体无关的胞吐小泡。这些结果表明，mTor参与调节tau在亚细胞器中的分布以及tau从细胞分泌到细胞外空间的起始过程。
