Redox-active iron mediates amyloid-beta toxicity.
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.
Rottkamp
C A
CA
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Raina
A K
AK
Zhu
X
X
Gaier
E
E
Bush
A I
AI
Atwood
C S
CS
Chevion
M
M
Perry
G
G
Smith
M A
MA
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
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D007501:Iron; D003676:Deferoxamine