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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Jing Wu1, Shan-Lei Zhou1, Lin-Hua Pi1, Xia-Jie Shi1, Ling-Ran Ma2, Zi Chen1, Min-Li Qu1, Xin Li2, Sheng-Dan Nie3, Duan-Fang Liao4, Jin-Jing Pei5,6,7 and Shan Wang1,2
1Department of Endocrinology, Xiang-Ya Hospital, Central South University, Changsha, Hunan, China
2Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, China
3Institute of Clinical Medicine, People’s Hospital of Hunan Province, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
4Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Traditional Chinese Medicine, Changsha, Hunan, China
5KI-Alzheimer’s Disease Research Center, Karolinska Institutet, Novum, Stockholm, Sweden
6Department of Neurology, Xuan Wu Hospital, Capital Medical University, Xicheng, Beijing, China
7Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China
Shan Wang, email: firstname.lastname@example.org
Jing Wu, email: email@example.com
Keywords: diabetes mellitus, cognitive dysfunction, caveolin-1, tau hyperphosphorylation, mTOR
Received: February 20, 2017 Accepted: April 07, 2017 Published: April 19, 2017
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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