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Tumor Necrosis Factor-α, Interleukin-1β, and Interferon-γ Stimulate γ-Secretase-mediated Cleavage of Amyloid Precursor Protein through a JNK-dependent MAPK Pathway
Open accessAbstract
The deposition of the amyloid beta (Abeta) peptide in neuritic plaques plays a critical role in the pathogenesis of Alzheimer's disease (AD). Abeta is generated through the proteolysis of amyloid precursor protein (APP) by the sequential actions of beta- and gamma-secretases. Although recent evidence has unveiled much about the biochemical identity and characteristics of gamma-secretase, the mechanism regulating endogenous gamma-secretase activity remains elusive. To identify possible extracellular signals and associated signaling cascades that could regulate APP proteolysis by gamma-secretase activity, we have developed a cell-based reporter gene assay by stably cotransfecting HEK293 cells with the Gal4-driven luciferase reporter gene and the Gal4/VP16-tagged C-terminal fragment of APP (C99-GV), the immediate substrate of gamma-secretase. The cleavage of C99-GV by gamma-secretase releases the transcription factor that activates luciferase expression, providing a quantitative measurement of gamma-secretase activity. Using this reporter assay, we have demonstrated that interferon-gamma, interleukin-1beta, and tumor necrosis factor-alpha can specifically stimulate gamma-secretase activity, concomitant with increased production of Abeta and the intracellular domain of APP (AICD). The gamma-secretase-dependent cleavage of Notch is also enhanced upon the stimulation of these cytokines. The cytokine-enhanced gamma-secretase activity can be suppressed by a potent inhibitor of c-Jun N-terminal kinase (JNK). Furthermore, cells transfected with dominant-positive MEKK1, one of the most potent activators of the JNK cascade, exhibit increased gamma-secretase activity, suggesting that the JNK-dependent mitogen-activated protein kinase pathway could mediate the cytokine-elicited regulation of gamma-secretase. Our studies provide direct evidence that cytokine-elicited signaling cascades control Abeta production by modulating gamma-secretase activity.
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“B94 (GenBank M92357) is a TNF-α-inducible proinflammatory element (Colangelo et al., 2002; Liao et al., 2004).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Liao et al., 2004
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“IL-1β directly stimulates γ-secretase-mediated cleavage of βAPP into Aβ peptides through a JNK-dependent MAPK pathway (Liao et al., 2004).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Liao et al., 2004
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Metadata
- Authors
- Liao, Y.-F., Wang, B.-J., Cheng, H.-T., Kuo, L.-H., & Wolfe, M. S.
- Affiliations
- Academia Sinica (TW)
- Brigham and Women's Hospital (US)
- Corresponding author
- Liao, Yung-Feng
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-11
- Volume
- 279
- Issue
- 47
- Pages
- 49523-49532
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1992680479
- Cited by
- 389
- References
- 57
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 29 · 2023: 28 · 2022: 25 · 2021: 21 · 2020: 22 · 2019: 16 · 2018: 14 · 2017: 12 · 2016: 13 · 2015: 13 · 2014: 15 · 2013: 25 · 2012: 14
- FWCI
- 9.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Science Council
- Academia Sinica
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- gamma-secretase, amyloid precursor protein, amyloid-beta, Alzheimer's disease, TNF-α, IL-1β, interferon-gamma, JNK, MAPK signaling, MEKK1, Notch cleavage, APP intracellular domain, cytokine signaling
- MeSH terms
- Animals, Cell Line, DNA, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Genes, Dominant, Humans, Interferon-gamma, Interleukin-1, Luciferases, Membrane Proteins, Mutation, Endopeptidases, Transfection, Tumor Necrosis Factor-alpha, Blotting, Western, Signal Transduction, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Culture Media, Serum-Free, Protein Structure, Tertiary, Genes, Reporter, COS Cells, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Receptors, Notch, Amyloid Precursor Protein Secretases
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