PPARgamma transcriptionally regulates the expression of insulin-degrading enzyme in primary neurons

Insulin-degrading enzyme (IDE) is a protease that has been demonstrated to play a key role in degrading both Abeta and insulin and deficient in IDE function is associated with Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2) pathology. However, little is known about the cellular and molecular regulation of IDE expression. Here we show IDE levels are markedly decreased in DM2 patients and positively correlated with the peroxisome proliferator-activated receptor gamma (PPARgamma) levels. Further studies show that PPARgamma plays an important role in regulating IDE expression in rat primary neurons through binding to a functional peroxisome proliferator-response element (PPRE) in IDE promoter and promoting IDE gene transcription. Finally, we demonstrate that PPARgamma participates in the insulin-induced IDE expression in neurons. These results suggest that PPARgamma transcriptionally induces IDE expression which provides a novel mechanism for the use of PPARgamma agonists in both DM2 and AD therapies.