Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ
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- Magdalena Sastre
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Ilse Dewachter
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Steffen Rossner
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Nenad Bogdanovic
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Evan Rosen
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Peter Borghgraef
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Bernd O. Evert
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Lucia Dumitrescu-Ozimek
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Dietmar R. Thal
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Gary Landreth
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Jochen Walter
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Thomas Klockgether
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Fred van Leuven
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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- Michael T. Heneka
- Departments of Neurology and Neuropathology, University of Bonn, Sigmund Freud Strasse 25, 53127 Bonn, Germany; Experimental Genetics Group, Department of Human Genetics, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium; Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, 04109 Leipzig, Germany; Karolinska Institute, Neurotec, Geriatric Department and Huddinge Brain Bank KFC, Novum, Plan4, 14186 Stockholm, Sweden;...
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説明
<jats:p> 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 <jats:italic>in vivo</jats:italic> 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. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 103 (2), 443-448, 2006-01-03
Proceedings of the National Academy of Sciences