Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1).
In mammalian brain, O-GlcNAc modification of Tau decreases its phosphorylation and toxicity, suggesting a neuroprotective role of pharmacological elevation of brain O-GlcNAc for Alzheimer's disease treatment.
More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease.