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

2006; National Academy of Sciences; Volume: 103; Issue: 2 Linguagem: Inglês

10.1073/pnas.0503839103

1091-6490

Magdalena Sastre, Ilse Dewachter, Steffen Roßner, Nenad Bogdanović, Evan D. Rosen, Peter Borghgraef, Bernd O. Evert, Lucia Dumitrescu‐Ozimek, Dietmar Rudolf Thal, Gary E. Landreth, Jochen Walter, Thomas Klockgether, Fred Van Leuven, Michael T. Heneka,

Alzheimer's disease research and treatments

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-γ (PPARγ), which is a nuclear transcriptional regulator. Here we show that PPARγ depletion potentiates β-secretase [β-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARγ, as well as NSAIDs and PPARγ activators, reduced BACE1 gene promoter activity. These results suggested that PPARγ could be a repressor of BACE1. We then identified a PPARγ responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARγ to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARγ gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARγ agonists increased PPARγ and reduced BACE1 mRNA and intracellular β-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARγ expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARγ in the modulation of amyloid-β generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARγ and decreased BACE1 gene transcription.