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SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis
Author(s) -
Kim Dohoon,
Nguyen Minh Dang,
Dobbin Matthew M,
Fischer Andre,
Sananbenesi Farahnaz,
Rodgers Joseph T,
Delalle Ivana,
Baur Joseph A,
Sui Guangchao,
Armour Sean M,
Puigserver Pere,
Sinclair David A,
Tsai LiHuei
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601758
Subject(s) - amyotrophic lateral sclerosis , neurodegeneration , biology , neuroscience , disease , alzheimer's disease , medicine
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.