O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease

Fei Liu, Khalid Iqbal, Inge Grundke-Iqbal, Gerald Warren Hart, Cheng Xin Gong

Research output: Contribution to journalArticlepeer-review

Abstract

Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains of individuals with Alzheimer's disease (AD) and other tauopathies. Tau pathology is critical to pathogenesis and correlates to the severity of dementia. However, the mechanisms leading to abnormal hyperphosphorylation are unknown. Here, we demonstrate that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide β-N-acetylglucosamine (GlcNAc) attaches to serine/threonine residues via an O-linked glycosidic bond. O-GlcNAcylation regulated phosphorylation of tau in a site-specific manner both in vitro and in vivo. At most of the phosphorylation sites, O-GlcNAcylation negatively regulated tau phosphorylation. In an animal model of starved mice, low glucose uptake/metabolism that mimicked those observed in AD brain produced a decrease in O-GlcNAcylation and consequent hyperphosphorylation of tau at the majority of the phosphorylation sites. The O-GlcNAcylation level in AD brain extracts was decreased as compared to that in controls. These results reveal a mechanism of regulation of tau phosphorylation and suggest that abnormal hyperphosphorylation of tau could result from decreased tau O-GlcNAcylation, which probably is induced by deficient brain glucose uptake/metabolism in AD and other tauopathies.

Original languageEnglish (US)
Pages (from-to)10804-10809
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number29
DOIs
StatePublished - Jul 20 2004

ASJC Scopus subject areas

  • Genetics
  • General

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