Epidemiological evidence suggests that nonsteroidal anti-inflam-matory drugs (NSAIDs) decrease the risk for Alzheimer’s disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor- (cid:2) (PPAR (cid:2) ), which is a nuclear transcriptional regulator. Here we show that PPAR (cid:2) depletion potentiates (cid:1) secretase [ (cid:1) -site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPAR (cid:2) , as well as NSAIDs and PPAR (cid:2) activators, reduced BACE1 gene promoter activity. These results suggested that PPAR (cid:2) could be a repressor of BACE1. We then identified a PPAR (cid:2) responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPAR (cid:2) to the PPRE and increased BACE1 gene promoter activity. cytokines decreased PPAR (cid:2) gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPAR (cid:2) agonists increased PPAR (cid:2) and reduced BACE1 mRNA and intracellular (cid:1) -amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPAR (cid:2) expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPAR (cid:2) in the modulation of amyloid- (cid:1) generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPAR (cid:2) and decreased BACE1 gene transcription. and Dr. for generous gifts of antibodies and cells; Dr. Chi-cago) for providing cells; Dr. for PPAR (cid:2) antagonist GW0072; Dr. for APPsw cDNA; for PPAR- (cid:2) 1 cDNA; Dr. for mouse PPAR (cid:2) 2- E499Q cDNA; for human PPAR (cid:2) 2 cDNA; and Dr. Knethen for the PPAR (cid:2) responsive element (PPRE) reporter plasmid. This investigation was supported by the Sonderforschungsbereich 400 [SFB 400, Teilprojekt A8 (to M.T.H. and T.K.) and DFG WA1477 (cid:3) 3 (to J.W.)], by Fonds voor Wetenschappelijk Onderzoek Vlaanderen, by the Katholieke Leuven Research Fund, and by Katholieke Universiteit Leuven Research and Development. I.D. is a postdoctoral fellow at Fonds voor Wetenschappelijk Onderzoek Vlaanderen.