High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction

Oncotarget. 2017 Jun 20;8(25):40843-40856. doi: 10.18632/oncotarget.17257.

Abstract

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.

Keywords: caveolin-1; cognitive dysfunction; diabetes mellitus; mTOR; tau hyperphosphorylation.

MeSH terms

  • Animals
  • Caveolin 1 / metabolism*
  • Cognitive Dysfunction / metabolism*
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / psychology*
  • Glucose / administration & dosage
  • Glucose / metabolism
  • Hyperglycemia / metabolism
  • Hyperglycemia / psychology
  • Male
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • TOR Serine-Threonine Kinases / metabolism*
  • Transfection
  • tau Proteins / metabolism*

Substances

  • Cav1 protein, rat
  • Caveolin 1
  • tau Proteins
  • mTOR protein, rat
  • TOR Serine-Threonine Kinases
  • Glucose