Open AccessNonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ
Author(s) -
Magdalena Sastre,
Ilse Dewachter,
Steffen Rößner,
Nenad Bogdanović,
Evan D. Rosen,
Peter Borghgraef,
Bernd O. Evert,
Lucia Dumitrescu-Ozimek,
Dietmar Rudolf Thal,
Gary E. Landreth,
Jochen Walter,
Thomas Klockgether,
Freddy Van Leuven,
Michael T. Heneka
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0503839103
Subject(s) - peroxisome proliferator activated receptor , promoter , amyloid precursor protein secretase , chemistry , repressor , microbiology and biotechnology , response element , gene expression , transcription (linguistics) , amyloid precursor protein , receptor , gene , biology , biochemistry , medicine , alzheimer's disease , disease , linguistics , philosophy
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 thatin 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.