Redox-active iron mediates amyloid-beta toxicity

While amyloid-beta toxicity is mediated by oxidative stress and can be atte nuated by antioxidants, the actual biochemical mechanism underlying neuroto xicity remains to be established. However, since aggregated amyloid-beta ca n interact with transition metals, such as iron, both in vitro and in vivo, we suspected that bound iron might be the mediator of toxicity such that h olo- and apo-amyloid would have differential effects on cellular viability. Here we demonstrate that when amyloid-beta is pretreated with the iron che lator deferoxamine, neuronal toxicity is significantly attenuated while con versely, incubation of holo-amyloid-beta with excess free iron restores tox icity to original levels. These data, taken together with the known sequela e of amyloid-beta, suggest that the toxicity of amyloid-beta is mediated, a t least in part, via redox-active iron that precipitates lipid peroxidation and cellular oxidative stress. (C) 2001 Elsevier Science Inc.