Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation.

Abstract

Abnormal hyperphosphorylation of microtubule-associated protein tau plays a crucial role in neurodegeneration in Alzheimer's disease (AD). The aggregation of hyperphosphorylated tau into neurofibrillary tangles is also a hallmark brain lesion of AD. Tau phosphorylation is regulated by tau kinases, tau phosphatases, and O-GlcNAcylation, a posttranslational modification of proteins on the serine or threonine residues with β-N-acetylglucosamine (GlcNAc). O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase, the enzyme catalyzing the transfer of GlcNAc to proteins, and N-acetylglucosaminidase (OGA), the enzyme catalyzing the removal of GlcNAc from proteins. Thiamet-G is a recently synthesized potent OGA inhibitor, and initial studies suggest it can influence O-GlcNAc levels in the brain, allowing OGA inhibition to be a potential route to altering disease progression in AD. In this study, we injected thiamet-G into the lateral ventricle of mice to increase O-GlcNAcylation of proteins and investigated the resulting effects on site-specific tau phosphorylation. We found that acute thiamet-G treatment led to a decrease in tau phosphorylation at Thr181, Thr212, Ser214, Ser262/Ser356, Ser404 and Ser409, and an increase in tau phosphorylation at Ser199, Ser202, Ser396 and Ser422 in the mouse brain. Investigation of the major tau kinases showed that acute delivery of a high dose of thiamet-G into the brain also led to a marked activation of glycogen synthase kinase-3β (GSK-3β), possibly as a consequence of down-regulation of its upstream regulating kinase, AKT. However, the elevation of tau phosphorylation at the sites above was not observed and GSK-3β was not activated in cultured adult hippocampal progenitor cells or in PC12 cells after thiamet-G treatment. These results suggest that acute high-dose thiamet-G injection can not only directly antagonize tau phosphorylation, but also stimulate GSK-3β activity, with the downstream consequence being site-specific, bi-directional regulation of tau phosphorylation in the mammalian brain.

• Authors: Yang Yu, Lan Zhang, Xiaojing Li, Xiaoqin Run, Zhihou Liang, Yi Li, Ying Liu, Moon H Lee, Inge Grundke-Iqbal, Khalid Iqbal, David J Vocadlo, Fei Liu, Cheng-Xin Gong
• Journal: PloS one (PLoS One) Vol. 7 Issue 4 Pg. e35277 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22536363 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrans
• Thiazoles
• tau Proteins
• thiamet G
• Protein Kinases
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3
• hexosaminidase C
• beta-N-Acetylhexosaminidases

Topics

• Acylation
• Animals
• Brain (cytology, drug effects, metabolism)
• Cells, Cultured
• Enzyme Activation (drug effects)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Male
• Mice
• Mice, Transgenic
• Neurons (drug effects, enzymology, metabolism)
• Phosphorylation
• Protein Kinases (metabolism)
• Protein Processing, Post-Translational (drug effects)
• Pyrans (pharmacology)
• Rats
• Thiazoles (pharmacology)
• beta-N-Acetylhexosaminidases (antagonists & inhibitors, metabolism)
• tau Proteins (metabolism)