Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models

Abstract

Curcumin is a polyphenolic diketone from turmeric. Because of its anti-oxidant and anti-inflammatory effects, it was tested in animal models of Alzheimer's disease, reducing levels of amyloid and oxidized proteins and preventing cognitive deficits. An alternative mechanism of these effects is metal chelation, which may reduce amyloid aggregation or oxidative neurotoxicity. Metals can induce Aβ aggregation and toxicity, and are concentrated in AD brain. Chelators desferrioxamine and clioquinol have exhibited anti-AD effects. Using spectrophotometry, we quantified curcumin affinity for copper, zinc, and iron ions. Zn²⁺ showed little binding, but each Cu²⁺ or Fe²⁺ ion appeared to bind at least two curcumin molecules. The interaction of curcumin with copper reached half-maximum at ∼3–12 μM copper and exhibited positive cooperativity, with K_d1∼10–60 μM and K_d2∼1.3 μM (for binding of the first and second curcumin molecules, respectively). Curcumin-iron interaction reached half-maximum at ∼2.5–5 μM iron and exhibited negative cooperativity, with K_d1∼0.5–1.6 μM and K_d2∼50–100 μM. Curcumin and its metabolites can attain these levels in vivo, suggesting physiological relevance. Since curcumin more readily binds the redox-active metals iron and copper than redox-inactive zinc, curcumin might exert a net protective effect against Aβ toxicity or might suppress inflammatory damage by preventing metal induction of NF-κB.