Effects of 4-hydroxy-nonenal and amyloid-β on expression and activity of endothelin converting enzyme and insulin degrading enzyme in SH-SY5Y cells

The cerebral accumulation of amyloid-β (Aβ) 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 Aβ accumulation. Although endothelin converting enzyme (ECE) and insulin degrading enzyme (IDE) degrade and thus contribute to regulating the steady-state levels of Aβ, how these enzymes are regulated remain poorly understood. In this study, we investigated the effects of 4-hydroxy-nonenal (HNE) and Aβ on the expression and activity of ECE-1 and IDE in human neuroblastoma SH-SY5Y cells. Treatment with HNE or Aβ upregulated ECE-1 mRNA and protein, while IDE was unchanged. Although both ECE-1 and IDE were oxidized within 24 h of HNE or Aβ 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 Aβ. In addition, the results suggest complex mechanisms underlying the regulation of their enzymatic activity.