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.