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Papers In Press, published online ahead of print December 7, 2004
GRECC (VA Medical) and Medicine, University of California Los Angeles, North Hills, CA 91343
Corresponding Author: gmcole{at}ucla.edu
Alzheimer's disease (AD) involves amyloid (A
J. Biol. Chem, 10.1074/jbc.M404751200
Submitted on April 28, 2004
Revised on December 6, 2004
Accepted on December 7, 2004
Curcumin inhibits formation of A
oligomers and fibrils and binds plaques and reduces amyloid in vivo
) 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 Aß-binding, we investigated whether its efficacy in AD models could be explained by effects on Aß aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC50 =0.8 µM) as well as disaggregated fibrillar Aß40 (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 0.1-1.0 
M. Under electron microscopy, curcumin decreased dose-dependently Aß fibril formation beginning with 0.125 µM. Curcumin's effects 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 ß-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Aß as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.
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