Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Emmanuel Planel, Tomohiro Miyasaka, Thomas Launey, De Hua Chui, Kentaro Tanemura, Shinji Sato, Ohoshi Murayama, Koichi Ishiguro, Yoshitaka Tatebayashi, Akihiko Takashima

Research output: Contribution to journalArticle

192 Citations (Scopus)

Abstract

Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein. Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.

Original languageEnglish
Pages (from-to)2401-2411
Number of pages11
JournalJournal of Neuroscience
Volume24
Issue number10
DOIs
Publication statusPublished - 2004 Mar 10
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Diabetes mellitus
  • GSK-3
  • Glucose metabolism
  • Hypothermia
  • Insulin
  • JNK
  • Kinase
  • MAPK
  • Serine-threonine protein phosphatase
  • Tau hyperphosphorylation
  • cdk5

ASJC Scopus subject areas

  • Neuroscience(all)

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