It has been established for a long time that brain glucose metabolism is 
impaired in Alzheimer's disease. Recent studies have demonstrated that impaired 
brain glucose metabolism precedes the appearance of clinical symptoms, implying 
its active role in the development of Alzheimer's disease. However, the 
molecular mechanism by which this impairment contributes to the disease is not 
known. In this study, we demonstrated that protein O-GlcNAcylation, a common 
post-translational modification of nucleocytoplasmic proteins with 
beta-N-acetyl-glucosamine and a process regulated by glucose metabolism, was 
markedly decreased in Alzheimer's disease cerebrum. 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. We also found that 
hyperphosphorylated tau contained 4-fold less O-GlcNAc than 
non-hyperphosphorylated tau, demonstrating for the first time an inverse 
relationship between O-GlcNAcylation and phosphorylation of tau in the human 
brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase 
with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. 
Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in 
decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled 
changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with 
decreased glucose metabolism induced by fasting, but not those in rat brains 
when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation 
patterns under various conditions suggests that abnormal tau 
hyperphosphorylation in Alzheimer's disease brain may result from downregulation 
of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that 
impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau 
and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in 
Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein 
phosphatase 2A activity may offer promising therapeutic targets for treating 
Alzheimer's disease.