Reversible inactivation of superoxide-sensitive aconitase in A beta 1-42-treated neuronal cell lines

The activity of the superoxide-sensitive enzyme aconitase was monitored to evaluate the generation of superoxide in neuronal cell lines treated with b eta-amyloid (A beta) peptide 1-42. Treatment of differentiated and undiffer entiated rat PC12 and human neuroblastoma SK-N-SH cells with soluble A beta 1-42 (A beta-derived diffusible ligands) or fibrillar A beta 1-42 caused a 35% reversible inactivation of aconitase, which preceded loss of viability and was correlated with altered cellular function. Aconitase was reactivat ed upon incubation of cellular extracts with iron and sulfur, suggesting th at A beta causes the release of iron from 4Fe-4S clusters. A beta neurotoxi city was partially blocked by the iron chelator deferoxamirne. These data s uggest that increased superoxide generation and the release of iron from 4F e-4S clusters are early events in A beta 1-42 neurotoxicity.