Reversible Inactivation of Superoxide-Sensitive Aconitase in Aβ1-42-Treated Neuronal Cell Lines

Abstract: The activity of the superoxide-sensitive enzyme aconitase was monitored to evaluate the generation of superoxide in neuronal cell lines treated with β-amyloid (Aβ) peptide 1-42. Treatment of differentiated and undifferentiated rat PC12 and human neuroblastoma SK-N-SH cells with soluble Aβ1-42 (Aβ-derived diffusible ligands) or fibrillar Aβ1-42 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 Aβ causes the release of iron from 4Fe-4S clusters. Aβ neurotoxicity was partially blocked by the iron chelator deferoxamine. These data suggest that increased superoxide generation and the release of iron from 4Fe-4S clusters are early events in Aβ1-42 neurotoxicity.