دورية أكاديمية
The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
| العنوان: | The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130 |
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| المؤلفون: | Müller, Stephan A., Shmueli, Merav D., Lichtenthaler, Stefan F., Feng, Xiao, Tüshaus, Johanna, Schumacher, Neele, Clark, Ryan, Smith, Brad E., Chi, An, Rose-John, Stefan, Kennedy, Matthew E. |
| المصدر: | Molecular neurodegeneration 18(1), 13 (2023). doi:10.1186/s13024-023-00596-6 |
| بيانات النشر: | Biomed Central |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | info:eu-repo/classification/ddc/570, Mice, Humans, Animals, Alzheimer Disease: drug therapy, Amyloid Precursor Protein Secretases, Cytokine Receptor gp130: therapeutic use, Aspartic Acid Endopeptidases, Interleukin-6, Nerve Tissue Proteins, IL-6 receptor subunit beta, IL-6R, Secretase, Shedding, Trans-signaling, VCAM1, Cytokine Receptor gp130, BACE1 protein, human, Sez6 protein, mouse |
| جغرافية الموضوع: | DE |
| الوصف: | The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates.To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors.Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal.BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/issn/1750-1326; info:eu-repo/semantics/altIdentifier/pmid/pmid:36810097; https://pub.dzne.de/record/255485Test; https://pub.dzne.de/search?p=id:%22DZNE-2023-00286%22Test |
| الإتاحة: | https://doi.org/10.1186/s13024-023-00596-6Test https://pub.dzne.de/record/255485Test https://pub.dzne.de/search?p=id:%22DZNE-2023-00286%22Test |
| حقوق: | info:eu-repo/semantics/closedAccess |
| رقم الانضمام: | edsbas.CCD0D2C5 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |