High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction.
High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction.
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高糖通过 Cav-1-mTOR 通路诱导 tau 蛋白过度磷酸化形成：糖尿病引起认知功能障碍的潜在分子机制
DOI：
10.18632/oncotarget.17257
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发表时间：
2017-06-20
期刊：
影响因子：
--
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Wu J;Zhou SL;Pi LH;Shi XJ;Ma LR;Chen Z;Qu ML;Li X;Nie SD;Liao DF;Pei JJ;Wang S
异常过度磷酸化的tau被认为与糖尿病相关的认知障碍有关。哺乳动物靶标雷帕霉素(MTOR)/S6K(S6K)信号通路在tau过度磷酸化形成中的作用已有研究。小窝蛋白-1(Cav-1)是小窝的基本结构蛋白，可促进神经元的存活和生长，抑制糖代谢。本研究旨在探讨Cav-1在慢性高血糖状态下tau蛋白过度磷酸化形成中的作用。用链脲佐菌素(STZ)诱导糖尿病大鼠。原代培养的海马神经元在有或没有分子干预的情况下，如一过性过度表达或敲除，接受HGC。采用实时定量RT-PCR、Western印迹、免疫荧光或免疫组织化学等方法对实验样品进行分析。我们发现：1)慢性HGC直接降低糖尿病大鼠脑神经元Cav-1的表达，增加tau的磷酸化，激活mTOR/S6K信号；2)Cav-1的过度表达减弱慢性HGC诱导的原代海马神经元tau的过度磷酸化，而利用Cav-1 siRNA下调Cav-1通过mTOR/S6K信号通路显著恶化tau的过度磷酸化；3)HGC诱导的Cav-1的下调不依赖mTOR信号转导。我们的结果提示，高血糖下tau蛋白过度磷酸化和持续过度激活的mTOR信号可能是由于抑制Cav-1所致。因此，Cav-1是治疗糖尿病认知功能障碍的潜在靶点。
The abnormally hyperphosphorylated tau is thought to be implicated in diabetes-associated cognitive deficits. The role of mammalian target of rapamycin (mTOR) / S6 kinase (S6K) signalling in the formation of tau hyperphosphorylation has been previously studied. Caveolin-1 (Cav-1), the essential structure protein of caveolae, promotes neuronal survival and growth, and inhibits glucose metabolism. In this study, we aimed to investigate the role of Cav-1 in the formation of tau hyperphosphorylation under chronic hyperglycemic condition (HGC). Diabetic rats were induced by streptozotocin (STZ). Primary hippocampal neurons with or without molecular intervention such as the transient over-expression or knock-down were subjected to HGC. The obtained experimental samples were analyzed by real time quantitative RT-PCR, Western blot, immunofluorescence or immunohistochemisty. We found: 1) that a chronic HGC directly decreases Cav-1 expression, increases tau phosphorylation and activates mTOR/S6K signalling in the brain neurons of diabetic rats, 2) that overexpression of Cav-1 attenuates tau hyperphosphorylation induced by chronic HGC in primary hippocampal neurons, whereas down-regulation of Cav-1 using Cav-1 siRNA dramatically worsens tau hyperphosphorylation via mTOR/S6K signalling pathway, and 3) that the down-regulation of Cav-1 induced by HGC is independent of mTOR signalling. Our results suggest that tau hyperphosphorylation and the sustained over-activated mTOR signalling under hyperglycemia may be due to the suppression of Cav-1. Therefore, Cav-1 is a potential therapeutic target for diabetes-induced cognitive dysfunction.
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影响因子：
--
作者：
Kang Q;Xiang Y;Li D;Liang J;Zhang X;Zhou F;Qiao M;Nie Y;He Y;Cheng J;Dai Y;Li Y
通讯作者：
Li Y
DOI：
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发表时间：
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影响因子：
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作者：
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影响因子：
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通讯作者：
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