Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting.
Impaired brain glucose uptake/metabolism precedes the symptoms of Alzheimer disease (AD) and is likely to play a role in the development of the disease, but the mechanism by which it contributes to AD is not understood. Because glucose uptake/metabolism regulates protein O-GlcNAcylation, and the latter modulates phosphorylation of tau inversely, we investigated, in fasting Kunming mice, whether impaired brain glucose uptake/metabolism causes abnormal hyperphosphorylation of tau and, consequently, facilitates the neurofibrillary degeneration of AD via down-regulation of tau O-GlcNAcylation. We found that fasting caused decreased tau O-GlcNAcylation and concurrent hyperphosphorylation of tau at most of the phosphorylation sites studied. The hippocampus was found more vulnerable to the tau alterations than the cerebral cortex, which is consistent with the fact that it is the hippocampus that is first affected in AD. 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 contributes to AD and suggest that it may be feasible to treat AD by reversing the abnormal hyperphosphorylation of tau at early stages of the disease.
Li
Xu
X
Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P.R. China.
Lu
Fen
F
Wang
Jian-Zhi
JZ
Gong
Cheng-Xin
CX
D000215:Acylation; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism*; D005215:Fasting; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010766:Phosphorylation; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase