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Media type:
E-Article
Title:
The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
Contributor:
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.
Published:
Springer Science and Business Media LLC, 2023
Published in:
Molecular Neurodegeneration, 18 (2023) 1
Language:
English
DOI:
10.1186/s13024-023-00596-6
ISSN:
1750-1326
Origination:
Footnote:
Description:
Abstract 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