Tau — a protein involved in Alzheimer's disease — is modified by O-linked N-acetylglucosamine (O-GlcNAc). This study investigated the effect of thiamet G, an inhibitor of the glycoside hydrolase O-GlcNAcase, in a mouse model of Alzheimer's disease (hemizygous JNPL3 mice). Oral treatment of mice increased tau-specific O-GlcNAc in the brain, hindered the formation of tau aggregates and decreased neuronal cell loss. Furthermore, O-GlcNAc modification blocked tau oligomerization independently of tau phosphorylation, and also inhibited the aggregation of an unrelated protein, suggesting that O-GlcNAc may function to prevent protein aggregation in general.
ORIGINAL RESEARCH PAPER
Yuzwa, S. A. et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nature Chem. Biol. 26 Feb 2012 (doi:10.1038/nchembio.797)
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Inhibiting tau oligomerization. Nat Rev Drug Discov 11, 274 (2012). https://doi.org/10.1038/nrd3711
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DOI: https://doi.org/10.1038/nrd3711