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

Molecular Neurodegeneration

Research Article

Stefan Rose-John¹  Neele Schumacher¹  An Chi²  Merav D. Shmueli³  Xiao Feng³  Johanna Tüshaus³  Stephan A. Müller³  Stefan F. Lichtenthaler⁴  Brad E. Smith⁵  Ryan Clark⁶  Matthew E. Kennedy⁶ 

[1] Biochemical Institute, Kiel University, Kiel, Germany;Chemical Biology, Merck & Co. Inc., Boston, MA, USA;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany;German Center for Neurodegenerative Diseases (DZNE), Munich, Germany;Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany;Munich Cluster for Systems Neurology (SyNergy), Munich, Germany;Laboratory Animal Resources, Merck & Co. Inc., West Point, PA, USA;Neuroscience, Merck & Co. Inc., Boston, MA, USA;

关键词: IL-6 receptor subunit beta;    Secretase;    IL-6R;    Shedding;    Trans-signaling;    VCAM1;   

DOI  :  10.1186/s13024-023-00596-6

 received in 2022-08-09, accepted in 2023-01-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsTo identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors.ResultsBesides 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.ConclusionBACE1 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.Graphical abstract

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

40517_2023_248_Article_IEq10.gif

40517_2023_248_Article_IEq4.gif

Fig. 1

Fig. 13

Fig. 5

Fig. 2

Fig. 1

13690_2023_1046_Article_IEq6.gif

Fig. 1

Fig. 6

Fig. 5

Fig. 4

Fig. 4

Fig. 2