Neuronal SIRT1 Activation as a Novel Mechanism Underlying the Prevention of Alzheimer Disease Amyloid Neuropathology by Calorie Restriction
Open accessAbstract
Nicotinamide adenine dinucleotide (NAD)+-dependent sirtuins have been identified to be key regulators in the lifespan extending effects of calorie restriction (CR) in a number of species. In this study we report for the first time that promotion of the NAD+-dependent sirtuin, SIRT1-mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of beta-amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, known in part for its role in the inhibition of the non-amyloidogenic alpha-secretase processing of the amyloid precursor protein. Conversely, we found that the expression of constitutively active ROCK1 in vitro cultures significantly prevented SIRT1-mediated response, suggesting that alpha-secretase activity is required for SIRT1-mediated prevention of AD-type amyloid neuropathology. Consistently we found that the expression of exogenous human (h) SIRT1 in the brain of hSIRT1 transgenics also resulted in decreased ROCK1 expression and elevated alpha-secretase activity in vivo. These results demonstrate for the first time a role for SIRT1 activation in the brain as a novel mechanism through which CR may influence AD amyloid neuropathology. The study provides a potentially novel pharmacological strategy for AD prevention and/or treatment.
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Increased intracellular NAD+ concentration activates SIRT1 in brain following caloric restriction and this results in a reduction in amyloid pathology in a mouse model of Alzheimer disease.
“Increased intracellular NAD+ concentration activates SIRT1 in brain following caloric restriction and this results in a reduction in amyloid pathology in a mouse model of Alzheimer disease197.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [197]
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- Authors
- Qin, W., Yang, T., Ho, L., Zhao, Z., Wang, J., Chen, L., Zhao, W., Thiyagarajan, M., MacGrogan, D., Rodgers, J. T., Puigserver, P., Sadoshima, J., Deng, H., Pedrini, S., Gandy, S., Sauve, A. A., & Pasinetti, G. M.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Cornell University (US)
- Mount Sinai Hospital (US)
- Johns Hopkins University (US)
- Rutgers New Jersey Medical School (US)
- Rockefeller University (US)
- Corresponding author
- Sauve, Anthony A.
- Pasinetti, Giulio M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 281
- Issue
- 31
- Pages
- 21745-21754
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2161678021
- Cited by
- 626
- References
- 31
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 15 · 2023: 25 · 2022: 31 · 2021: 36 · 2020: 33 · 2019: 23 · 2018: 35 · 2017: 28 · 2016: 27 · 2015: 26 · 2014: 33 · 2013: 35 · 2012: 34
- FWCI
- 25.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01AG010491)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- SIRT1, caloric restriction, Alzheimer's disease, amyloid-beta, ROCK1, Rho kinase, alpha-secretase, amyloid precursor protein, Alzheimer's disease prevention
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Enzyme Activation, Female, Humans, Mice, Inbred Strains, Mice, Transgenic, Neurons, Endopeptidases, Aspartic Acid Endopeptidases, Protein Serine-Threonine Kinases, Caloric Restriction, Sirtuins, Intracellular Signaling Peptides and Proteins, Mice, Amyloid Precursor Protein Secretases, rho-Associated Kinases, Sirtuin 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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