engMüller, Stephan ALichtenthaler, StefanDataset: Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibitionThe protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive 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 a new 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. In 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.PRoteomics IDEntifications Database (2023).info:eu-repo/semantics/researchdatainfo:eu-repo/semantics/publishedVersionPRoteomics IDEntifications Database2023info:eu-repo/semantics/closedAccessDEhttps://pub.dzne.de/record/279497https://pub.dzne.de/search?p=id:%22DZNE-2025-00824%22Researchers