engMüller, Stephan A.Shmueli, Merav D.Lichtenthaler, Stefan F.Feng, XiaoTüshaus, JohannaSchumacher, NeeleClark, RyanSmith, Brad E.Chi, AnRose-John, StefanKennedy, Matthew E.The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130info:eu-repo/classification/ddc/570MiceHumansAnimalsAlzheimer Disease: drug therapyAmyloid Precursor Protein SecretasesCytokine Receptor gp130: therapeutic useAspartic Acid EndopeptidasesInterleukin-6Nerve Tissue ProteinsIL-6 receptor subunit betaIL-6RSecretaseSheddingTrans-signalingVCAM1Amyloid Precursor Protein SecretasesCytokine Receptor gp130Aspartic Acid EndopeptidasesInterleukin-6BACE1 protein, humanSez6 protein, mouseNerve Tissue ProteinsBace1 protein, mouseThe 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.Molecular neurodegeneration 18(1), 13 (2023). doi:10.1186/s13024-023-00596-6info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionBiomed Central2023info:eu-repo/semantics/openAccessDEhttps://pub.dzne.de/record/255485https://pub.dzne.de/search?p=id:%22DZNE-2023-00286%22Researchersinfo:eu-repo/semantics/altIdentifier/issn/1750-1326info:eu-repo/semantics/altIdentifier/doi/10.1186/s13024-023-00596-6info:eu-repo/semantics/altIdentifier/pmid/pmid:36810097