title: Redox-active iron mediates amyloid-beta toxicity.
abstract: While amyloid-beta toxicity is mediated by oxidative stress and can be attenuated by antioxidants, the actual biochemical mechanism underlying neurotoxicity remains to be established. However, since aggregated amyloid-beta can 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 holo- and apo-amyloid would have differential effects on cellular viability. Here we demonstrate that when amyloid-beta is pretreated with the iron chelator deferoxamine, neuronal toxicity is significantly attenuated while conversely, incubation of holo-amyloid-beta with excess free iron restores toxicity to original levels. These data, taken together with the known sequelae of amyloid-beta, suggest that the toxicity of amyloid-beta is mediated, at least in part, via redox-active iron that precipitates lipid peroxidation and cellular oxidative stress.
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Rottkamp
authors.forename: A K
authors.initials: AK
authors.lastname: Raina
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.forename: E
authors.initials: E
authors.lastname: Gaier
authors.forename: A I
authors.initials: AI
authors.lastname: Bush
authors.forename: C S
authors.initials: CS
authors.lastname: Atwood
authors.forename: M
authors.initials: M
authors.lastname: Chevion
authors.forename: G
authors.initials: G
authors.lastname: Perry
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000502:physiology*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D007501:Iron; D003676:Deferoxamine