RGD Reference Report - Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. - Rat Genome Database

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Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction.

Authors: Qin, W  Yang, T  Ho, L  Zhao, Z  Wang, J  Chen, L  Zhao, W  Thiyagarajan, M  MacGrogan, D  Rodgers, JT  Puigserver, P  Sadoshima, J  Deng, H  Pedrini, S  Gandy, S  Sauve, AA  Pasinetti, GM 
Citation: Qin W, etal., J Biol Chem. 2006 Aug 4;281(31):21745-54. Epub 2006 Jun 2.
RGD ID: 10047116
Pubmed: PMID:16751189   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M602909200   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease treatmentISOSirt1 (Mus musculus)10047116; 10047116 RGD 
Alzheimer's disease treatmentIDA 10047116 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Sirt1  (sirtuin 1)

Genes (Mus musculus)
Sirt1  (sirtuin 1)

Genes (Homo sapiens)
SIRT1  (sirtuin 1)


Additional Information