Nonsteroidal anti-inflammatory drugs repress [beta]-secretase gene promoter activity by the activation of PPAR[gamma]

Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-[gamma], (PPAR[gamma]), which is a nuclear transcriptional regulator. Here we show that PPAR[gamma], depletion potentiates [beta]-secretase [[beta]-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 PPAR[gamma] 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 PPAR[gamma] 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. amyloid | inflammation | Alzheimer's disease | transgenic mice