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Experimental Genetics Group
Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):443-8. Sastre M1*, Dewachter I2, Rossner S3, Bogdanovic N4, Rosen E5, Borghgraef P2, Evert BO1, Dumitrescu-Ozimek L1, Thal DR6, Landreth G7, Walter J1, Klockgether T1, van Leuven F2, Heneka MT1*. 1Department of Neurology, University of Bonn, Bonn, Germany. 2Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium. 3Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Leipzig, Germany. 4Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Stockholm, Sweden. 5Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA. 6Department of Neuropathology, University of Bonn, Bonn, Germany. 7Alzheimer Laboratory, case Western Reserve University, Cleveland, OH. *Corresponding authors. 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.  FULL TEXT |
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