The cerebral accumulation of amyloid-beta (Abeta) is a consistent feature of and likely contributor to the development of Alzheimer's disease (AD). In addition to dysregulated production, increasing experimental evidence suggests reduced catabolism plays an important role in Abeta accumulation. Although endothelin converting enzyme (ECE) and insulin degrading enzyme (IDE) degrade and thus contribute to regulating the steady-state levels of Abeta, how these enzymes are regulated remain poorly understood. In this study, we investigated the effects of 4-hydroxy-nonenal (HNE) and Abeta on the expression and activity of ECE-1 and IDE in human neuroblastoma SH-SY5Y cells. Treatment with HNE or Abeta upregulated ECE-1 mRNA and protein, while IDE was unchanged. Although both ECE-1 and IDE were oxidized within 24 h of HNE or Abeta treatment, ECE-1 catalytic activity was elevated while IDE specific activity was unchanged. The results demonstrated for the first time that both ECE-1 and IDE are substrates of HNE modification induced by Abeta. In addition, the results suggest complex mechanisms underlying the regulation of their enzymatic activity.