The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

"availability of data and materials the mass spectrometry proteomics data of the mbi-4 study have been deposited to the proteomexchange consortium via the pride [ 111 ] partner repository with the dataset identifier pxd035141. compared to the vehicle group the single dose of 100 mg/kg (mpk) mbi-4 significantly reduced the csf abundance of the ectodomain of three proteins (sez6 il6st/gp130 vcam1) to 25-50% at 24 h post-dosing when applying false discovery rate correction [ ] (fig 1 b supplementary data 1 ) sez6 is a known bace1 substrate [ ] whereas vcam1 is a substrate for bace2 in glial cells [ ] which do not express bace1 il6st is the cytokine receptor gp130 and was previously suggested as a potential bace1 substrate candidate in two proteomic studies using non-neuronal cell lines [ ] but was not further studied.; additional file 2: supplementary data 1.; additional file 3: supplementary data 2."

"Declarations Ethics approval and consent to participateAll mouse work conducted in the frame work of this project was performed according to the European Communities Council Directive (86/609/EEC) and was approved by the committee responsible for animal ethics of the government of Upper Bavaria (02–19-067) and in accordance to the criteria outlined by the German governments (Ministerium für Energiewende, Landwirtschaft, Umwelt und ländliche Räume Schleswig-Holstein). BACE1−/− and control mice were breed in the pathogen-free animal facilities of the Center for Stroke and Dementia Research (CSD) in Munich or the animal facility of Kiel University (Victor-Hensen-Haus).All animal procedures of experiments with NHP were done in accordance with guidelines from the Institutional Animal Care and Use Committee at Merck.The human clinical study was conducted in accordance with International Conference on Harmonisation Good Clinical Practice guidelines and was approved by the relevant institutional review boards. Written informed consent was provided by the patients or their legal representatives. The full details of the study and study protocol were previously published [27]. Competing interestsRC, BS, AC and MEK are employees of Merck. SR-J has acted as a consultant and speaker for Abb-Vie, Chugai, Genentech Roche, Roche, Pfizer, and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein Olamkicept together with the companies Ferring Pharmaceuticals and I-Mab. SR-J has stock ownership in CONARIS. All other authors declare no competing interests. Competing interests RC, BS, AC and MEK are employees of Merck. SR-J has acted as a consultant and speaker for Abb-Vie, Chugai, Genentech Roche, Roche, Pfizer, and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein Olamkicept together with the companies Ferring Pharmaceuticals and I-Mab. SR-J has stock ownership in CONARIS. All other authors declare no competing interests."

"Funding Open Access funding enabled and organized by Projekt DEAL. Research was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy– ID 390857198) and the consortium FOR2290, and the Bundesministerium für Bildung und Forschung (JPND PMG AD and CLINSPECT-M) (to SFL). The work of SR-J was funded by DFG (project number 80750187—SFB 841 (project C1)), project number 125440785—SFB 877 (projects A1 and A14), by the Deutsche Krebshilfe, by the German Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ and by the German-Israeli Foundation for Scientific Research and Development."