Reversible inactivation of superoxide-sensitive aconitase in Aβ1-42-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 beta-amyloid (A beta) peptide 1-42. Treatment of differentiated and undifferentiated 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 reactivated upon incubation of cellular extracts with iron and sulfur, suggesting that A beta causes the release of iron from 4Fe-4S clusters. A beta neurotoxicity was partially blocked by the iron chelator deferoxamirne. These data suggest that increased superoxide generation and the release of iron from 4Fe-4S clusters are early events in A beta 1-42 neurotoxicity.