279497 20260107145434.0 DZNE-2025-00824 Müller, Stephan A P:(DE-2719)2810938 0 dzne Dataset: Pharmacoproteomics of non-human primate cerebrospinal fluid after BACE inhibition 2023 PRoteomics IDEntifications Database MISC BibTeX Dataset dataset dataset PUB:(DE-HGF)32 1752047420_8072 PUB:(DE-HGF) Chart or Table 26 EndNote Dataset DataCite DATA_SET ORCID ResearchData DINI The 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Lichtenthaler, Stefan P:(DE-2719)2181459 1 dzne Müller, Stephan A. et.al. London : Biomed Central, 2023 RelatedTo DZNE-2023-00286 The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130 https://wwwdev.ebi.ac.uk/pride/archive/projects/PXD035141 oai:pub.dzne.de:279497 VDB Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2810938 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 1 P:(DE-2719)2181459 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2023 I:(DE-2719)1110006 AG Lichtenthaler Neuroproteomics 0 dataset VDB I:(DE-2719)1110006 UNRESTRICTED