Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3

Mark A. Lovell, Shuling Xiong, Chengsong Xie, Peter Davies, William R. Markesbery

Research output: Contribution to journalArticlepeer-review

166 Scopus citations

Abstract

Neurofibrillary tangles (NFT) containing paired helical filaments (PHF) composed of abnormally phosphorylated tau are one of the hallmark lesions of the Alzheimer's disease (AD) brain. Although phosphorylation of tau is thought to precede the formation of PHF, the kinases/phosphatases involved remain poorly understood. Here we report that treatment of primary rat cortical neuron cultures with cuprizone, a copper chelator, in combination with oxidative stress (Fe2+/H2O2), significantly increased aberrant tau phosphorylation identified by TG3 immunochemistry. To determine the potential contribution of glycogen synthase kinase-3 (GSK-3) to the phosphorylation of tau in this model, activity of GSK-3 was determined. Cultures treated with cuprizone/Fe2+/H2O2 showed significantly increased GSK-3 activity compared with control cultures or cultures treated with cuprizone, or Fe2+/H2O2 alone. Concomitant treatment of cultures with lithium, a GSK-3 inhibitor, significantly decreased GSK-3 activity and reduced TG3 staining. Together these data suggest a culture model of hyperphosphorylated tau that implicates increased GSK-3 activity.

Original languageEnglish
Pages (from-to)659-671
Number of pages13
JournalJournal of Alzheimer's Disease
Volume6
Issue number6
DOIs
StatePublished - 2004

Keywords

  • cortical neuron culture
  • glycogen synthase kinase-3
  • hyperphosphorylated tau
  • paired helical filaments

ASJC Scopus subject areas

  • Neuroscience (all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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