255485 20240403131748.0 pmc:PMC9942414 pmc 10.1186/s13024-023-00596-6 doi altmetric:142765972 altmetric pmid:36810097 pmid DZNE-2023-00286 English 570 Müller, Stephan A. P:(DE-2719)2810938 0 First author The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130 London 2023 Biomed Central article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1711028350_32504 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote CC BY 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 DFG project 390857198 - EXC 2145: Munich Cluster for Systems Neurology (SyNergy) (390857198) G:(GEPRIS)390857198 390857198 1 Dataset connected to CrossRef, Journals: pub.dzne.de IL-6 receptor subunit beta Other IL-6R Other Secretase Other Shedding Other Trans-signaling Other VCAM1 Other Amyloid Precursor Protein Secretases EC 3.4.- NLM Chemicals Cytokine Receptor gp130 133483-10-0 NLM Chemicals Aspartic Acid Endopeptidases EC 3.4.23.- NLM Chemicals Interleukin-6 NLM Chemicals BACE1 protein, human EC 3.4.23.46 NLM Chemicals Sez6 protein, mouse NLM Chemicals Nerve Tissue Proteins NLM Chemicals Bace1 protein, mouse EC 3.4.23.46 NLM Chemicals Mice MeSH Humans MeSH Animals MeSH Alzheimer Disease: drug therapy MeSH Amyloid Precursor Protein Secretases MeSH Cytokine Receptor gp130: therapeutic use MeSH Aspartic Acid Endopeptidases MeSH Interleukin-6 MeSH Nerve Tissue Proteins MeSH Shmueli, Merav D. P:(DE-2719)2812458 1 Feng, Xiao P:(DE-2719)9000546 2 Tüshaus, Johanna P:(DE-2719)2812852 3 Schumacher, Neele P:(DE-HGF)0 4 Clark, Ryan P:(DE-HGF)0 5 Smith, Brad E. P:(DE-HGF)0 6 Chi, An P:(DE-HGF)0 7 Rose-John, Stefan P:(DE-HGF)0 8 Kennedy, Matthew E. P:(DE-HGF)0 9 Lichtenthaler, Stefan F. P:(DE-2719)2181459 10 Last author 10.1186/s13024-023-00596-6 Vol. 18, no. 1, p. 13 PERI:(DE-600)2244557-2 1 13 Molecular neurodegeneration 18 2023 1750-1326 OpenAccess http://pub.dzne.de/record/255485/files/DZNE-2023-00286.pdf OpenAccess pdfa http://pub.dzne.de/record/255485/files/DZNE-2023-00286.pdf?subformat=pdfa oai:pub.dzne.de:255485 openaire open_access VDB driver dnbdelivery 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)2812458 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)9000546 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-2719)2812852 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 10 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 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2023-10-25 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2023-10-25 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2023-10-25 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2022-11-23 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2023-10-25 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2023-04-12T15:09:14Z WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2022-11-23 DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2023-04-12T15:09:14Z DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2023-10-25 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2023-10-25 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC OpenAccess StatID:(DE-HGF)0510 StatID Peer Review StatID:(DE-HGF)0030 StatID ASC 2023-10-25 Article Processing Charges StatID:(DE-HGF)0561 StatID 2022-11-23 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2022-11-23 DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central 2023-10-25 Fees StatID:(DE-HGF)0700 StatID 2022-11-23 Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Anonymous peer review 2023-04-12T15:09:14Z I:(DE-2719)1110006 AG Lichtenthaler Neuroproteomics 0 journal VDB UNRESTRICTED I:(DE-2719)1110006 FullTexts