Liu Zan-Chao, Chu Jiang, Lin Li, Song Jie, Ning Lin-Na, Luo Hong-Bin, Yang Shu-Sheng, Shi Yan, Wang Qun, Qu Na, Zhang Qi, Wang Jian-Zhi, Tian Qing
Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College; Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute of Brain Science, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China.
2nd Hospital of Shijiazhuang, Shijiazhuang, 050051, China.
Mol Neurobiol. 2016 Mar;53(2):983-994. doi: 10.1007/s12035-014-9039-4. Epub 2015 Jan 10.
Endoplasmic reticulum (ER) stress has been indicated in the early stage of Alzheimer's disease (AD), in which tau hyperphosphorylation is one major pathological alteration. The elevation of binding immunoglobulin protein (Bip), an important ER chaperon, was reported in AD brain. It is important to study the roles of ER-related chaperons in tau hyperphosphorylation. In this research, increased Bip was found in the brains of the AD model mice (Tg2576) compared to the age-matched control mice. Meanwhile, deficiency of SIL1, an important co-chaperon of Bip, was observed in brains of Tg2576 mice and in ER stress both in vivo and in vitro. Then, we transfected Bip-EGFP plasmid into HEK293 cells stably expressing the longest human tau (HEK293/tau) or N2a cells and found that increased Bip induced tau hyperphosphorylation via activating glycogen synthase kinase-3β (GSK-3β), an important tau kinase, and increased the association with tau and GSK-3β. When we overexpressed SIL1 in Bip-transfected HEK293/tau cells and thapsigargin-treated HEK293/tau cells, significantly reduced tau hyperphosphorylation and GSK-3β activation were observed. These results suggested the important roles of ER-related chaperons, Bip and SIL1, in AD-like tau hyperphosphorylation.
内质网（ER）应激已在阿尔茨海默病（AD）的早期阶段被发现，其中tau蛋白过度磷酸化是一个主要的病理改变。据报道，在AD脑内，重要的内质网伴侣蛋白——结合免疫球蛋白蛋白（Bip）水平升高。研究内质网相关伴侣蛋白在tau蛋白过度磷酸化中的作用具有重要意义。在本研究中，与年龄匹配的对照小鼠相比，在AD模型小鼠（Tg2576）的脑中发现Bip增加。同时，在Tg2576小鼠的脑中以及在体内和体外的内质网应激中均观察到Bip的重要共伴侣蛋白SIL1缺乏。然后，我们将Bip-EGFP质粒转染到稳定表达最长人tau蛋白的HEK293细胞（HEK293/tau）或N2a细胞中，发现增加的Bip通过激活重要的tau激酶糖原合酶激酶-3β（GSK-3β）诱导tau蛋白过度磷酸化，并增加了与tau和GSK-3β的结合。当我们在转染Bip的HEK293/tau细胞和毒胡萝卜素处理的HEK293/tau细胞中过表达SIL1时，观察到tau蛋白过度磷酸化和GSK-3β激活显著降低。这些结果表明内质网相关伴侣蛋白Bip和SIL1在类似AD的tau蛋白过度磷酸化中起重要作用。
