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J. Biol. Chem., Vol. 280, Issue 45, 37377-37382, November 11, 2005

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Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid- Peptides^*

From the Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, North Shore-Long Island Jewish Institute for Medical Research, Manhasset, New York 11030

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 remain 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- (A) peptides produced from different cell lines. Resveratrol does not inhibit A production, because it has no effect on the A-producing enzymes - and -secretases, but promotes instead intracellular degradation of A via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of A could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit 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.

Received for publication, July 27, 2005 , and in revised form, September 12, 2005.

^* This work was supported by National Institute of Mental Health Grant 38623 and by a grant from the American Health Assistance Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: The Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, North Shore-Long Island Jewish Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030. Tel.: 516-562-3492; E-mail: pmaramba{at}aecom.yu.edu.

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