Peroxisome Proliferator-Activated Receptor Gamma Enhances the Activity of an Insulin Degrading Enzyme-Like Metalloprotease for Amyloid-β

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) activation results in an increased rate of amyloid-β (Aβ) clearance from the media of diverse cells in culture, including primary neurons and glial cells. Here, we further investigate the mechanism for Aβ clearance and found that PPARγ activation modulates a cell surface metalloprotease that can be inhibited by metalloprotease inhibitors, like EDTA and phenanthroline, and also by the peptide hormones insulin and glucagon. The metalloprotease profile of the Aβ-degrading mechanism is surprisingly similar to insulin-degrading enzyme (IDE). This mechanism is maintained in hippocampal and glia primary cultures from IDE loss-of-function mice. We conclude that PPARγ activates an IDE-like Aβ degrading activity. Our work suggests a drugable pathway that can clear Aβ peptide from the brain.