Article
- The EMBO Journal (2007) 26, 3169 - 3179
- doi:10.1038/sj.emboj.7601758
Published online: 21 June 2007
Subject Categories:
SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis
Dohoon Kim1,2,a, Minh Dang Nguyen3,ab, Matthew M Dobbin1, Andre Fischer1,c, Farahnaz Sananbenesi1,c, Joseph T Rodgers4,5, Ivana Delalle1, Joseph A Baur6, Guangchao Sui3, Sean M Armour6, Pere Puigserver4,5, David A Sinclair6 and Li-Huei Tsai1
- Howard Hughes Medical Institute, Picower Insitute for Learning and Memory, Riken-MIT Neuroscience Research Center, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Boston, MA, USA
- Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
- Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Boston, MA, USA
- Department of Pathology and Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA, USA
Correspondence to:
Li-Huei Tsai, Tsai Brain and Cognitive Sciences, Massachusetts Institute of Technology, 32 Vassar Street, Boston, MA 02139, USA. Tel.: +1 617 324 1660; Fax: +1 617 324 1657; E-mail: lhtsai@mit.edu
David A Sinclair, Department of Pathology and Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston MA 02115, USA. Tel.: +1 617 432 3931; Fax: +1 617 432 6225; E-mail: david_sinclair@hms.harvard.edu
aThese authors contributed equally to this work
bPresent address: Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Heritage Medical Building, Room 150, Alberta, Canada T2N 4N1
cPresent address: European Neuroscience Institute (ENI), Medical School Georgia Augusta University Goettingen, Max Planck Society, Germany
Received 11 July 2006; Accepted 22 May 2007
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.
Keywords:
- AD,
- ALS,
- neurodegeneration,
- p25,
- SIRT1
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