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M602909200v1
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Papers In Press, published online ahead of print June 2, 2006
J. Biol. Chem, 10.1074/jbc.M602909200
Submitted on March 28, 2006
Revised on May 30, 2006
Accepted on June 2, 2006

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

Weiping Qin, Tianle Yang, Lap Ho, Zhong Zhao, Jun Wang, Linghong Chen, Meenakshisundaram Thiyagarajan, Donal MacGrogan, Joseph T. Rodgers, Pere Puigserver, Junichi Sadoshima, Haiteng Deng H., Steven Pedrini, Samuel Gandy, Anthony Sauve, and Giulio M. Pasinetti

Psychiatry, Mount Sinai School of Medicine, New York, NY 10029

Corresponding Author: giulio.pasinetti{at}mssm.edu

Nicotinamide adenine dinucleotide (NAD)+r-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+r-dependent sirtuin, SIRT1 mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer’s disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of beta -amyloid (Abeta ) 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 (APP). 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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