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Cited by 373Alzheimer's disease research and treatmentsPeroxisome Proliferator-Activated ReceptorsNeuroinflammation and Neurodegeneration Mechanisms

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

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Sastre, Magdalena, Dewachter, Ilse, Rossner, Steffen, Bogdanovic, Nenad, Rosen, Evan, Borghgraef, Peter, Evert, Bernd O., Dumitrescu-Ozimek, Lucia +6 more·2006·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0503839103PMC PMC1326151
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Abstract

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.

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Authors
Sastre, M., Dewachter, I., Rossner, S., Bogdanovic, N., Rosen, E., Borghgraef, P., Evert, B. O., Dumitrescu-Ozimek, L., Thal, D. R., Landreth, G., Walter, J., Klockgether, T., van Leuven, F., & Heneka, M. T.
Affiliations
  • University of Bonn (DE)
  • 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;...
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2006-01-03
Volume
103
Issue
2
Pages
443-448
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0503839103
PMC
PMC1326151
OpenAlex
W2147486806
Cited by
373
References
38
Citations by year
2026: 3 · 2025: 7 · 2024: 6 · 2023: 10 · 2022: 13 · 2021: 22 · 2020: 11 · 2019: 13 · 2018: 12 · 2017: 14 · 2016: 16 · 2015: 15 · 2014: 24 · 2013: 22 · 2012: 19
FWCI
23.42
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
  • Document Server@UHasselt (UHasselt) (submittedVersion)
Funders
  • Thomas Jefferson University
  • Technische Universität Kaiserslautern
  • Deutsche Forschungsgemeinschaft (SFB400)
  • KU Leuven
  • Université de Lausanne
  • Vlaamse regering
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
nonsteroidal anti-inflammatory drugs, PPARγ, BACE1, beta-secretase, Alzheimer's disease, gene promoter activity, transcriptional repression, inflammatory cytokines, amyloid-beta production, neuroinflammation, PPARγ agonists
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Anti-Inflammatory Agents, Non-Steroidal, Brain, Cells, Cultured, Female, Humans, Ibuprofen, Male, Middle Aged, Endopeptidases, Promoter Regions, Genetic, Transcription, Genetic, Down-Regulation, Cytokines, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Knockout, PPAR gamma, Mice, Rats, Amyloid Precursor Protein Secretases

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