17 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. AG Lichtenthaler The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130 Molecular neurodegeneration Molecular neurodegeneration Biomed Central London 1750-1326 10.1186/s13024-023-00596-6 English 13 1 18 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. CC BY ; 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 Amyloid Precursor Protein Secretases Cytokine Receptor gp130 Aspartic Acid Endopeptidases Interleukin-6 BACE1 protein, human Sez6 protein, mouse Nerve Tissue Proteins Bace1 protein, mouse Journal Article 2023 DZNE-2023-00286 2023 pmc:PMC9942414 pmid:36810097 https://pub.dzne.de/record/255485 https://doi.org/10.1186/s13024-023-00596-6