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