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J. Biol. Chem., Vol. 280, Issue 7, 5892-5901, February 18, 2005

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Curcumin Inhibits Formation of Amyloid Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo^*

Fusheng Yang, Giselle P. Lim, Aynun N. Begum, Oliver J. Ubeda, Mychica R. Simmons, Surendra S. Ambegaokar, Pingping P. Chen, Rakez Kayed¶, Charles G. Glabe¶, Sally A. Frautschy||, and Gregory M. Cole||**

From the Department of Medicine, UCLA, Los Angeles, California 90095, the Greater Los Angeles Veterans Affairs Healthcare System, Geriatric Research Education and Clinical Center, Sepulveda, California 91343, the ^||Department of Neurology, UCLA, Los Angeles, California 90095, and the ^¶Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900

Alzheimer's disease (AD) involves amyloid (A) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential A binding, we investigated whether its efficacy in AD models could be explained by effects on A aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC₅₀ = 0.8 µM) as well as disaggregated fibrillar A40 (IC₅₀ = 1 µM), indicating favorable stoichiometry for inhibition. Curcumin was a better A40 aggregation inhibitor than ibuprofen and naproxen, and prevented A42 oligomer formation and toxicity between 0.1 and 1.0 µM. Under EM, curcumin decreased dose dependently A fibril formation beginning with 0.125 µM. The effects of curcumin did not depend on A sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small -amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates A as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.

Received for publication, April 28, 2004 , and in revised form, December 6, 2004.

^* This work was supported by the Siegel Life Foundation (to S. A. F. and G. M. C.), National Institute of Neurological Disorders and Stroke Grant NS43946 (to G. M. C.), a Veterans Affairs Merit award (to G. M. C.), the Alzheimer Association (to G. M. C.), and UCLA Alzheimer's Disease Research Center Grant P50 AG 16570 (to G. M. C. and S. A. F.). 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.

^** To whom correspondence should be addressed: Greater Los Angeles VA Healthcare System GRECC11E, UCLA Depts. of Medicine and Neurology (SFVP), 16111 Plummer St., Sepulveda, CA 91343. Tel.: 818-891-7711 (ext. 9949); Fax: 818-895-5835; E-mail: gmcole{at}ucla.edu.

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