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Acetylation of tau inhibits its degradation and contributes to tauopathy.

Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated and that tau acetylation prevents degradation of phosphorylated tau (p-tau). We generated two antibodies specific for acetylated tau and showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy. Histone acetyltransferase p300 was involved in tau acetylation and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau, probably by blocking proteasome-mediated degradation. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Modulating tau acetylation could be a new therapeutic strategy to reduce tau-mediated neurodegeneration.

Pubmed ID: 20869593

Authors

  • Min SW
  • Cho SH
  • Zhou Y
  • Schroeder S
  • Haroutunian V
  • Seeley WW
  • Huang EJ
  • Shen Y
  • Masliah E
  • Mukherjee C
  • Meyers D
  • Cole PA
  • Ott M
  • Gan L

Journal

Neuron

Publication Data

September 23, 2010

Associated Grants

  • Agency: NIA NIH HHS, Id: AG023501-06
  • Agency: NCRR NIH HHS, Id: C06 RR018928
  • Agency: NIA NIH HHS, Id: P50 AG023501
  • Agency: NIA NIH HHS, Id: P50 AG023501-01
  • Agency: NIA NIH HHS, Id: R01 AG030207
  • Agency: NIA NIH HHS, Id: R01 AG030207-01A2
  • Agency: NIAID NIH HHS, Id: R01 AI083139

Mesh Terms

  • Acetylation
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Carbazoles
  • Cells, Cultured
  • Cerebral Cortex
  • Cycloheximide
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Gene Expression Regulation
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Mutation
  • Neurons
  • Phosphorylation
  • Protein Synthesis Inhibitors
  • Rats
  • Rats, Sprague-Dawley
  • Sirtuin 1
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Tauopathies
  • Time Factors
  • Transfection
  • Ubiquitination
  • p300-CBP Transcription Factors
  • tau Proteins