4-Hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau

Mark P. Mattson, Weiming Fu, Georg Waeg, Koji Uchida

Research output: Contribution to journalArticlepeer-review

Abstract

In Alzheimer's disease (AD) the microtubule-associated protein tau is excessively phosphorylated in degenerating neurons, but the mechanisms underlying the increased phosphorylation are unknown. Recent findings suggest that oxidative stress, and membrane lipid peroxidation in particular, contributes to the neurodegenerative process in AD. We now report that following exposure of cultured rat hippocampal neurons to 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, tau is resistant to dephosphorylation. Immunocytochemical and Western blot analyses using phosphorylation-sensitive tau antibodies showed that HNE treatment causes a moderate increase in basal levels of tau phosphorylation, and prevents tau dephosphorylation by alkaline phosphatase inhibitor okadaic acid. Studies with anti-HNE antibodies showed that HNE binds directly to tau, and that HNE immunoreactivity localizes to cell bodies and axons, cell compartments that contain tau. These data suggest a role for HNE in altered tau phosphorylation and neurofibrillary degeneration in AD.

Original languageEnglish (US)
Pages (from-to)2275-2281
Number of pages7
JournalNeuroReport
Volume8
Issue number9-10
StatePublished - 1997
Externally publishedYes

Keywords

  • Alkaline phosphatase
  • Alzheimer's disease
  • Confocal laser scanning microscopy
  • Okadaic acid

ASJC Scopus subject areas

  • Neuroscience(all)

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