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O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease
Open accessAbstract
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.
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“a reduction of glucose consumption induces an increase in phospho-Tau and A β accumulation (Fu et al., 2015; Liu et al., 2004).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Liu et al., 2004
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“For example, reduced tau O-glycosylation could lead to increased phosphorylation, while the enhancement of O-glycosylation reduces the extent of tau phosphorylation [43–45].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [43]
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“As discussed above, a reciprocal relationship has been found between O-GlcNAcylation and phosphorylation on tau [43].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [43]
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Metadata
- Authors
- Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G. W., & Gong, C.-X.
- Affiliations
- Johns Hopkins University (US)
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314; and Department of Biological Chemistry, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
- Corresponding author
- Gong, Cheng-Xin
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-07-12
- Volume
- 101
- Issue
- 29
- Pages
- 10804-10809
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC490015
- OpenAlex
- W2164029759
- Cited by
- 775
- References
- 42
- Citations by year
- 2026: 29 · 2025: 50 · 2024: 38 · 2023: 36 · 2022: 44 · 2021: 63 · 2020: 57 · 2019: 38 · 2018: 46 · 2017: 45 · 2016: 33 · 2015: 23 · 2014: 36 · 2013: 24 · 2012: 35
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Nanjing Medical University
- National Institutes of Health (HD13563)
- National Institute on Aging (AG19158, R01AG019158, AG16760, R01AG016760)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD013563, HD13563)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- O-GlcNAcylation, tau protein, tau hyperphosphorylation, Alzheimer's disease, tauopathy, neurofibrillary tangles, O-glycosylation, glucose metabolism, brain glucose uptake
- MeSH terms
- Acetylglucosamine, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Female, Glycosylation, Humans, Male, Mice, Inbred C57BL, Middle Aged, Phosphorylation, Starvation, PC12 Cells, tau Proteins, Rats, Wistar, Mice, Rats, In Vitro Techniques
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