SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis

Dohoon Kim, Minh Dang Nguyen, Matthew M. Dobbin, Andre Fischer, Farahnaz Sananbenesi, Joseph T. Rodgers, Ivana Delalle, Joseph A. Baur, Guangchao Sui, Sean M. Armour, Pere Puigserver, David A. Sinclair, Li Huei Tsai

    Research output: Contribution to journalArticle

    Abstract

    A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

    Original languageEnglish (US)
    Pages (from-to)3169-3179
    Number of pages11
    JournalThe EMBO journal
    Volume26
    Issue number13
    DOIs
    StatePublished - Jul 11 2007

    Keywords

    • AD
    • ALS
    • Neurodegeneration
    • p25
    • SIRT1

    ASJC Scopus subject areas

    • Genetics
    • Cell Biology

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  • Cite this

    Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M., Puigserver, P., Sinclair, D. A., & Tsai, L. H. (2007). SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. The EMBO journal, 26(13), 3169-3179. https://doi.org/10.1038/sj.emboj.7601758