التفاصيل البيبلوغرافية
| العنوان: |
The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130 |
| المؤلفون: |
Müller, Stephan A., Shmueli, Merav D., Feng, Xiao, Tüshaus, Johanna, Schumacher, Neele, Clark, Ryan, Smith, Brad E., Chi, An, Rose-John, Stefan, Kennedy, Matthew E., Lichtenthaler, Stefan F. |
| المساهمون: |
Klinikum rechts der Isar der Technischen Universität München |
| المصدر: |
Molecular Neurodegeneration ; volume 18, issue 1 ; ISSN 1750-1326 |
| بيانات النشر: |
Springer Science and Business Media LLC |
| سنة النشر: |
2023 |
| مصطلحات موضوعية: |
Cellular and Molecular Neuroscience, Neurology (clinical), Molecular Biology |
| الوصف: |
Background 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. Methods To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Results 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. Conclusion 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. Graphical abstract |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1186/s13024-023-00596-6 |
| DOI: |
10.1186/s13024-023-00596-6.pdf |
| DOI: |
10.1186/s13024-023-00596-6/fulltext.html |
| الإتاحة: |
https://doi.org/10.1186/s13024-023-00596-6Test |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: |
edsbas.DBA290C7 |
| قاعدة البيانات: |
BASE |
