SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.
Journal: 2007/November - EMBO Journal
ISSN: 0261-4189
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.
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EMBO J 26(13): 3169-3179

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

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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
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: ude.tim@iasthl
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: ude.dravrah.smh@rialcnis_divad
These authors contributed equally to this work
Present address: Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Heritage Medical Building, Room 150, Alberta, Canada T2N 4N1
Present address: European Neuroscience Institute (ENI), Medical School Georgia Augusta University Goettingen, Max Planck Society, Germany
Received 2006 Jul 11; Accepted 2007 May 22.

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
Abstract
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Acknowledgments

We thank Dr B Samuels for critical reading of the manuscript, Dr L Moy for helpful discussions, and Drs M Urushitani and J-P Julien for SOD1 constructs and mice. This work was supported by the National Institutes of Health (NIH) (DAS and L-HT), POI Grant (Poi {"type":"entrez-nucleotide","attrs":{"text":"AG027916","term_id":"7714053","term_text":"AG027916"}}AG027916) the National Institute of Aging (DAS), the Canadian Institutes of Health Research (MDN) and the Paul F Glenn Foundation for Medical Research (DAS). L-HT is an investigator at the Howard Hughes Medical Institute. DAS is an Ellison Medical Research Foundation fellow. MDN is the Investigator at the Brenda Strafford Foundation Chair in Alzheimer research and a recipient of a Career Development Award from the Human Frontier Science Program Organization. AF held a Humbolt post-doctoral fellowship. FS was a fellow of the DFG (German Research Organization). JB holds an American Heart Association postdoctoral fellowship.

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