O-GlcNAcylation Regulates Phosphorylation of Tau: A Mechanism Involved in Alzheimer's Disease

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 mecha...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-07, Vol.101 (29), p.10804-10809
Main Authors: Liu, Fei, Iqbal, Khalid, Grundke-Iqbal, Inge, Hart, Gerald W., Gong, Cheng-Xin, Hakomori, Sen-Itiroh
Format: Article
Language:English
Subjects:
Acetylglucosamine - metabolism
Aged
Aged, 80 and over
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Alzheimers disease
Animals
Antibodies
Biological Sciences
Brain - metabolism
Developmental disabilities
Female
Glycosylation
Gongs
Humans
In Vitro Techniques
Male
Mice
Mice, Inbred C57BL
Middle Aged
Neurology
PC12 Cells
Phosphorylation
Physiological regulation
Rats
Rats, Wistar
Starvation
tau Proteins - genetics
tau Proteins - metabolism
Tauopathies
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0400348101