To explore the role of impaired brain glucose uptake/metabolism in neurodegeneration of Alzheimer's disease (AD), the relationship between an impaired brain glucose uptake/metabolism (down-regulation of tau O-GlcNAcylation) and the abnormal hyperphosphorylation of tau was investigated in fasting mice. It was found that fasting caused reduction of tau O-GlcNAcylation and a concomitant increase of tau phosphorylation at several hyperphosphorylation sites as seen in AD brain. Furthermore, hyperphosphorylation of tau induced by fasting was reversible in the brain after re-feeding. These findings provide a novel mechanism explaining how impaired brain glucose uptake/metabolism may contribute to AD-like tau hyperphosphorylation and also suggest feasibility to treat AD by reversing abnormal hyperphosphorylation of tau at early stages of the disease.