Physiological regulation of tau phosphorylation during hibernation

Bo Su, Xinglong Wang, Kelly L. Drew, George Perry, Mark A. Smith, Xiongwei Zhu

Research output: Contribution to journalArticlepeer-review

Abstract

The microtubule-associated protein tau is abnormally hyperphosphorylated in the brains of individuals with Alzheimer disease and other tauopathies, and is believed to play a critical role in the pathogenesis of these diseases. While the mechanisms leading to abnormal tau phosphorylation remain elusive, the recent demonstration of reversible tau phosphorylation during hibernation provides an ideal physiological model to study this critical process in vivo. In this study, arctic ground squirrels (AGS) during hibernation were used to study mechanisms related to tau hyperphosphorylation. Our data demonstrate that tau is hyperphosphorylated at all six sites (S199, T205, S214, S262, S396, and S404) examined in hibernating AGS. Interestingly, only three of these sites (S199, S262, and S404) are dephosphorylated in aroused animals, suggesting a reversible phosphorylation at selective sites. Summer-active AGS demonstrated the lowest tau phosphorylation at all these sites. To explore the mechanisms underlying increased tau phosphorylation during hibernation, the expression level and enzyme activity of various potential tau kinases and protein phosphatases were examined. The kinetic analysis of enzyme activity at different temperatures revealed differential changes in enzyme activity with temperature decline. Specifically, increased protein kinase A activity, decreased protein phosphatase 2A activity, as well as substantial contribution from glycogen synthase kinase-3β, likely play a key role in increased tau phosphorylation during hibernation in AGS.

Original languageEnglish (US)
Pages (from-to)2098-2108
Number of pages11
JournalJournal of Neurochemistry
Volume105
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

Keywords

  • Hibernation
  • Protein kinase A
  • Protein phosphatase 2A
  • Reversible phosphorylation
  • Tau

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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