Insulin-degrading enzyme (IDE) is a protease that has been demonstrated to play a key role in degrading both A beta 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 (PPAR gamma) levels. Further studies show that PPAR gamma 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 PPAR gamma participates in the insulin-induced IDE expression in neurons. These results suggest that PPAR gamma transcriptionally induces IDE expression which provides a novel mechanism for the use of PPAR gamma agonists in both DM2 and AD therapies. (C) 2009 Elsevier Inc. All rights reserved.