NSAIDs repress BACE1 gene promoter activity by activation of PPARgamma

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