Abstract
Alzheimer's disease (AD) involves amyloid beta (Abeta) 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 Abeta binding, we investigated whether its efficacy in AD models could be explained by effects on Abeta aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC(50) = 0.8 microM) as well as disaggregated fibrillar Abeta40 (IC(50) = 1 microM), indicating favorable stoichiometry for inhibition. Curcumin was a better Abeta40 aggregation inhibitor than ibuprofen and naproxen, and prevented Abeta42 oligomer formation and toxicity between 0.1 and 1.0 microM. Under EM, curcumin decreased dose dependently Abeta fibril formation beginning with 0.125 microM. The effects of curcumin did not depend on Abeta 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 beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.
Highlights
Alzheimer’s disease (AD) involves amyloid  (A) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and antiinflammatory consumption
The results show that curcumin limits fibril formation even when added midway through the incubation, consistent with an impact on fibril maturation or dissolution
Fibril Conformation Required for Curcumin Binding—We have shown that curcumin can bind to plaques and block A aggregation as well as fibril and oligomer formation
Summary
Alzheimer’s disease (AD) involves amyloid  (A) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and antiinflammatory consumption. Curcumin directly binds small -amyloid species to block aggregation and fibril formation in vitro and in vivo. Like these polar A binding compounds, curcumin might be able to cross the blood-brain barrier and bind to amyloid and related aggregates In these studies, we used an in vitro model of A fibrillization protein; AD, Alzheimer’s disease; CR, Congo Red; dH2O, distilled H2O; BSA, bovine serum albumin; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine; ANOVA, analysis of variance; EM, electron microscopy; LDH, lactate dehydrogenase; NSAID, nonsteroidal antiinflammatory drug; HFIP, hexafluoroisopropanol. We demonstrate that curcumin can label plaques in vitro and in vivo, block toxicity of oligomers in vitro, and significantly reduce amyloid levels in aged Tg2576 mice (22 months old) fed a curcumin diet beginning at 17 months after established amyloid deposition
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