%0 Journal Article
%A Müller, Stephan A.
%A Shmueli, Merav D.
%A Feng, Xiao
%A Tüshaus, Johanna
%A Schumacher, Neele
%A Clark, Ryan
%A Smith, Brad E.
%A Chi, An
%A Rose-John, Stefan
%A Kennedy, Matthew E.
%A Lichtenthaler, Stefan F.
%T The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130
%J Molecular neurodegeneration
%V 18
%N 1
%@ 1750-1326
%C London
%I Biomed Central
%M DZNE-2023-00286
%P 13
%D 2023
%Z CC BY
%X 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.
%K Mice
%K Humans
%K Animals
%K Alzheimer Disease: drug therapy
%K Amyloid Precursor Protein Secretases
%K Cytokine Receptor gp130: therapeutic use
%K Aspartic Acid Endopeptidases
%K Interleukin-6
%K Nerve Tissue Proteins
%K IL-6 receptor subunit beta (Other)
%K IL-6R (Other)
%K Secretase (Other)
%K Shedding (Other)
%K Trans-signaling (Other)
%K VCAM1 (Other)
%K Amyloid Precursor Protein Secretases (NLM Chemicals)
%K Cytokine Receptor gp130 (NLM Chemicals)
%K Aspartic Acid Endopeptidases (NLM Chemicals)
%K Interleukin-6 (NLM Chemicals)
%K BACE1 protein, human (NLM Chemicals)
%K Sez6 protein, mouse (NLM Chemicals)
%K Nerve Tissue Proteins (NLM Chemicals)
%K Bace1 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC9942414
%$ pmid:36810097
%R 10.1186/s13024-023-00596-6
%U https://pub.dzne.de/record/255485