High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction
机构：[1]Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, China[2]Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, China[3]Institute of Clinical Medicine, People’s Hospital of Hunan Province, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China[4]Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Traditional Chinese Medicine, Changsha, Hunan, China[5]KI-Alzheimer’s Disease Research Center, Karolinska Institutet, Novum, Stockholm, Sweden[6]Department of Neurology, Xuan Wu Hospital, Capital Medical University, Xicheng, Beijing, China神经内科首都医科大学宣武医院[7]Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, China
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 downregulation 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.
基金：
the National Natural Science Foundation of China (No. 81170754, 81402915, 81470046, 81573480 and 81670771)
the Key Research and Development Program of Hunan Province (No.2016JC2071).
第一作者机构：[1]Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, China
通讯作者：
通讯机构：[1]Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, China[2]Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, China
推荐引用方式(GB/T 7714)：
Jing Wu,Shan-Lei Zhou,Lin-Hua Pi,et al.High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction[J].ONCOTARGET.2017,8(25):40843-40856.doi:10.18632/oncotarget.17257.
APA：
Jing Wu,Shan-Lei Zhou,Lin-Hua Pi,Xia-Jie Shi,Ling-Ran Ma...&Shan Wang.(2017).High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction.ONCOTARGET,8,(25)
MLA：
Jing Wu,et al."High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction".ONCOTARGET 8..25(2017):40843-40856
医学