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| Subject Categories: Neuroscience | Molecular Biology of Disease |
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| The EMBO Journal
(2007) 26, 3169–3179, doi:10.1038/sj.emboj.7601758 Published online 21 June 2007 |
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| SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis |
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| Dohoon Kim1, 2, 7, Minh Dang Nguyen3, 7, 8, Matthew M Dobbin1, Andre Fischer1, 9, Farahnaz Sananbenesi1, 9, Joseph T Rodgers4, 5, Ivana Delalle1, Joseph A Baur6, Guangchao Sui3, Sean M Armour6, Pere Puigserver4, 5, David A Sinclair6 and Li-Huei Tsai1 |
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1 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 2 Division of Medical Sciences, Harvard Medical School, Boston, MA, USA 3 Department of Pathology, Harvard Medical School, Boston, MA, USA 4 Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA 5 Department of Cell Biology, Johns Hopkins University School of Medicine, Boston, MA, USA 6 Department of Pathology and Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA, USA To whom correspondence should be addressed 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 7 These authors contributed equally to this work 8 Present address: Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Heritage Medical Building, Room 150, Alberta, Canada T2N 4N1 9 Present address: European Neuroscience Institute (ENI), Medical School Georgia Augusta University Goettingen, Max Planck Society, Germany Received 11 July 2006; Accepted 22 May 2007; Published online 21 June 2007. |
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| Abstract |
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| 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. |
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| Keywords: AD, ALS, neurodegeneration, p25, SIRT1 |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSNature News and Views (11 Sep 2003) Nature Genetics News and Views (01 Apr 2005) RESEARCHThe EMBO Journal Article Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes Nature Letters to Editor (29 Nov 2007) |
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