SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis
Open accessAbstract
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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SIRT1 activity is altered in ALS mouse models and in postmortem ALS tissue, but the direction of the change is disputed.
“SIRT1 activity is altered in mouse models of ALS and in postmortem tissue samples from ALS patients; however, the direction of change has been debated”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Kim et al., 2007
SIRT1 protects against amyloid-β toxicity in cell culture and against neurodegeneration in the p25/CDK5 mouse model, which mimics aspects of Alzheimer's disease pathology and tauopathy.
“SIRT1 also protects against amyloid-β toxicity in cell culture and neurodegeneration in the p25/CDK5 mouse model, which recapitulates aspects of Alzheimer’s disease pathology and tauopathy (88).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [88]
Increased SIRT1 protected against hippocampal degeneration in another mouse model of Alzheimer disease.
“Increased SIRT1 protected against hippocampal degeneration in another mouse model of Alzheimer disease194.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [194]
SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing acetylation of SIRT1 substrates PGC-1α and p53.
“SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing the acetylation of SIRT1 substrates PGC-1α and p53194.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [194]
Direct injection of SIRT1 lentivirus in the hippocampus of AD transgenic mice shows significant neuroprotection.
“In addition, direct injection of SIRT1 lentivirus in the hippocampus of AD transgenic mice shows significant neuroprotection194.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [194]
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- Authors
- Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M., Puigserver, P., Sinclair, D. A., & Tsai, L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Corresponding author
- Sinclair, David A
- Tsai, Li‐Huei
- ORCID
- Venue
- The EMBO Journal
- Published
- 2007-06-21
- Volume
- 26
- Issue
- 13
- Pages
- 3169-3179
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1914106
- OpenAlex
- W2100978260
- Cited by
- 1,074
- References
- 51
- Citations by year
- 2026: 15 · 2025: 31 · 2024: 28 · 2023: 43 · 2022: 39 · 2021: 63 · 2020: 63 · 2019: 56 · 2018: 56 · 2017: 57 · 2016: 54 · 2015: 65 · 2014: 85 · 2013: 70 · 2012: 76
- FWCI
- 28.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Heart Association
- Glenn Foundation for Medical Research
- Deutsche Forschungsgemeinschaft
- Fondation pour la Recherche Médicale
- National Institutes of Health (AG027916)
- Canadian Institutes of Health Research
- National Institute on Aging (P01AG027916)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- SIRT1, Sir2, neurodegeneration, Alzheimer's disease, amyotrophic lateral sclerosis, resveratrol, caloric restriction, aging, tauopathy, PGC-1α, p53, neuronal survival, hippocampus, learning disabilities
- MeSH terms
- Superoxide Dismutase-1, Resveratrol, Acetylation, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Animals, Cells, Cultured, Disease Models, Animal, Enzyme Activation, Gene Expression Regulation, Humans, Mice, Transgenic, Mutation, Nerve Degeneration, Stilbenes, Superoxide Dismutase, Tumor Suppressor Protein p53, Sirtuins, Cyclin-Dependent Kinase 5, Mice, Rats, Sirtuin 1
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