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A more recent version of this article appeared on November 11, 2005
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M508246200v1
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Papers In Press, published online ahead of print September 14, 2005
J. Biol. Chem, 10.1074/jbc.M508246200
Submitted on July 27, 2005
Revised on September 12, 2005
Accepted on September 14, 2005

Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides

Philippe Marambaud, Haitian Zhao, and Peter Davies

The Litwin-Zucker Research Center for the Study of Alzheimer’s Disease and Memory Disorders, North Shore-LIJ Institute for Medical Research, Manhasset, NY 11030

Corresponding Author: pmaramba{at}aecom.yu.edu

Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer’s disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer’s disease brain, remains to be clearly defined. Here we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta ) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, since it has no effect on the Abeta -producing enzymes beta - and gamma -secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Abeta could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit beta 5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer’s disease.


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