Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferatoractivated receptor-gamma (PPAR-gamma), which is a nuclear transcriptional regulator. Here we show that PPAR-gamma depletion potentiates beta-secretase [P-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPAR gamma, as well as NSAIDs and PPAR gamma activators, reduced BACE1 gene promoter activity. These results suggested that PPAR gamma could be a repressor of BACE1. We then identified a PPAR gamma responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARy to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPAR-gamma gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPAR gamma agonists increased PPAR-gamma and reduced BACE1 mRNA and intracellular beta-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARy expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPAR gamma in the modulation of amyloid-beta generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPAR gamma and decreased BACE1 gene transcription.