Abstract
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.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Analysis of Variance
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Animals
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Animals, Newborn
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Carbazoles / pharmacology
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Cells, Cultured
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Cerebral Cortex / cytology
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Cycloheximide / pharmacology
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Humans
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Immunoprecipitation / methods
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Mice
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Mice, Transgenic
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Models, Biological
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Mutation / genetics
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Neurons / drug effects
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Neurons / metabolism
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / methods
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Tauopathies / etiology*
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Tauopathies / genetics
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Tauopathies / metabolism*
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Time Factors
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Transfection / methods
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Ubiquitination / drug effects
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p300-CBP Transcription Factors / physiology
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tau Proteins / genetics
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tau Proteins / metabolism*
Substances
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6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
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Carbazoles
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Enzyme Inhibitors
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MAPT protein, human
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Protein Synthesis Inhibitors
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tau Proteins
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Cycloheximide
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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SIRT1 protein, human
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Sirtuin 1