Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation

Nat Chem Biol. 2012 Feb 26;8(4):393-9. doi: 10.1038/nchembio.797.


Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to prevent protein aggregation. These results also suggest O-GlcNAcase as a potential therapeutic target that could hinder progression of Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / chemistry
  • Acetylglucosamine / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Carbohydrate Conformation
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Mice
  • Mice, Transgenic
  • N-Acetylglucosaminyltransferases / antagonists & inhibitors
  • N-Acetylglucosaminyltransferases / metabolism
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation
  • Pyrans / pharmacology
  • Thiazoles / pharmacology
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Enzyme Inhibitors
  • Pyrans
  • Tab1 protein, mouse
  • Thiazoles
  • tau Proteins
  • thiamet G
  • N-Acetylglucosaminyltransferases
  • Acetylglucosamine