[en] 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 (PPARgamma), which is a nuclear transcriptional regulator. Here we show that PPARgamma depletion potentiates beta-secretase [beta-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARgamma, as well as NSAIDs and PPARgamma activators, reduced BACE1 gene promoter activity. These results suggested that PPARgamma could be a repressor of BACE1. We then identified a PPARgamma responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARgamma to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARgamma gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARgamma agonists increased PPARgamma and reduced BACE1 mRNA and intracellular beta-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARgamma expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARgamma in the modulation of amyloid-beta generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARgamma and decreased BACE1 gene transcription.
Disciplines :
Neurology
Author, co-author :
Sastre, Magdalena; Department of Neurology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany. magdalena.sastre@ukb.uni-bonn.de
Dewachter, Ilse; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Rossner, Steffen; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany
Bogdanovic, Nenad; Karolinska Institute, Geriatric Department, Huddinge Brain Bank KFC, 14186 Stockholm, Sweden
Rosen, Evan; Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
Borghgraef, Peter; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Evert, Bernd O; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Dumitrescu-Ozimek, Lucia; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Thal, Dietmar R; Department of Neuropathology, University of Bonn, 53127 Bonn, Germany
Landreth, Gary; Alzheimer Laboratory, Case Western Reserve University, Cleveland, OH 44106, United States
Walter, Jochen; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Klockgether, Thomas; Department of Neurology, University of Bonn, 53127 Bonn, Germany
van Leuven, Fred; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
HENEKA, Michael ; Department of Neurology, University of Bonn, 53127 Bonn, Germany ; Department of Neurology, University of Muenster, 48149 Muenster, Germany
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