Modulation of the Activity of the Insulin-Degrading Enzyme by Aβ Peptides

The insulin-degrading enzyme (IDE) is an evolutionarily conserved protease implicated in the degradation of insulin and amyloidogenic peptides. Most of the biochemical and biophysical characterization of IDE's catalytic activity has been conducted using solutions containing a single substrate, i.e., insulin or Aβ(1-40). IDE's activity toward a particular substrate, however, is likely to be influenced by the presence of other substrates. Here, we show by a kinetic assay based on insulin's helical circular dichroic signal and MALDI TOF mass spectrometry that Aβ peptides modulate IDE's activity toward insulin in opposing ways. Aβ(1-40) enhances IDE-dependent degradation of insulin, whereas Aβ(pyroE3-42), the most pathogenic pyroglutamate-modified Aβ peptide in AD, inhibits IDE's activity. Intriguingly, Aβ(pyroE3-42) also inhibits IDE's ability to degrade Aβ(1-40). Together, our results implicate Aβ peptides in the abnormal catabolism of IDE's key substrates.