Brain Advance Access originally published online on May 18, 2009
Brain 2009 132(7):1820-1832; doi:10.1093/brain/awp099
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Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease
1 Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA 2 Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PR China
Correspondence to: Cheng-Xin Gong, Department of Neurochemistry, New York State Institute for Basic Research, 1050 Forest Hill Road, Staten Island, New York 10314, USA E-mail: cxgong{at}mail.csi.cuny.edu
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 β-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.
Key Words: tau phosphorylation; O-GlcNAcylation; glucose metabolism; protein phosphatase 2A; neurofibrillary degeneration
Abbreviations: aCSF, artificial cerebrospinal fluid; AD P-tau, abnormally hyperphosphorylated tau isolated from Alzheimer's disease brain; AD-tau, non-hyperphosphorylated tau isolated from Alzheimer's disease brain; DON, 6-diazo-5-oxonorleucine; GFAT, glutamine:fructose-6-P amidotransferase; GFP, green fluorescence protein; GlcNAc, β-N-acetyl-glucosamine; GLUT, glucose transporter; HBP, hexosamine biosynthesis pathway; NFTs, neurofibrillary tangles; O-GlcNAc, O-linked-β-N-acetylglucosamine; OGT, O-GlcNAc transferase; PP2A, protein phosphatase 2A; shRNA, small hairpin RNA
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Received January 8, 2009. Revised March 10, 2009. Accepted March 11, 2009.
*Present address: Department of Psychiatry, Osaka University Graduate School of Medicine, 2-2, D3, Yamadaoka, Suita, Osaka, 565-0871, Japan