Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation
Abstract
Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to prevent protein aggregation. These results also suggest O-GlcNAcase as a potential therapeutic target that could hinder progression of Alzheimer's disease.
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Increases in tau O-GlcNAcylation inhibit tau aggregates and neuronal cell loss.
“Increases in tau O-GlcNAcylation inhibit tau aggregates and neuronal cell loss [174], indicating that O-GlcNAcylation modification can protect AD progression.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [174]
Inhibitors of O-GlcNAcase enzyme (OGA) like thiamet G increase tau glycosylation, reduce NFTs and neuronal cell death, improve motor behavior, and prolong survival of tau transgenic mice.
“Inhibitors of the O-GlcNAcase enzyme (OGA)-like thiamet G increase tau glycosylation, reduce NFTs and neuronal cell death, improve motor behavior, and prolong survival of tau transgenic mice [174, 220, 221].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [174]
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- Authors
- Yuzwa, S. A., Shan, X., Macauley, M. S., Clark, T., Skorobogatko, Y., Vosseller, K., & Vocadlo, D. J.
- Affiliations
- Simon Fraser University (CA)
- Scripps Research Institute (US)
- Drexel University (US)
- Corresponding author
- Vocadlo, David J
- Venue
- Nature Chemical Biology
- Published
- 2012-02-26
- Volume
- 8
- Issue
- 4
- Pages
- 393-399
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2040714286
- Cited by
- 611
- References
- 50
- Citations by year
- 2026: 28 · 2025: 41 · 2024: 44 · 2023: 49 · 2022: 41 · 2021: 58 · 2020: 59 · 2019: 34 · 2018: 50 · 2017: 50 · 2016: 38 · 2015: 22 · 2014: 47 · 2013: 27 · 2012: 21
- FWCI
- 25.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Physiology › 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-GlcNAc, tau protein, tau aggregation, neurodegeneration, Alzheimer's disease, O-GlcNAcase inhibitors, tau phosphorylation, protein oligomerization, neuronal loss, therapeutic target
- MeSH terms
- Acetylglucosamine, Alzheimer Disease, Animals, Carbohydrate Conformation, Disease Models, Animal, Enzyme Inhibitors, Female, Humans, Mice, Transgenic, Neurons, Phosphorylation, Pyrans, Thiazoles, tau Proteins, N-Acetylglucosaminyltransferases, Neurodegenerative Diseases, Adaptor Proteins, Signal Transducing, Mice
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