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@ARTICLE{Mller:255485,
      author       = {Müller, Stephan A. and Shmueli, Merav D. and Feng, Xiao
                      and Tüshaus, Johanna and Schumacher, Neele and Clark, Ryan
                      and Smith, Brad E. and Chi, An and Rose-John, Stefan and
                      Kennedy, Matthew E. and Lichtenthaler, Stefan F.},
      title        = {{T}he {A}lzheimer’s disease-linked protease {BACE}1
                      modulates neuronal {IL}-6 signaling through shedding of the
                      receptor gp130},
      journal      = {Molecular neurodegeneration},
      volume       = {18},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2023-00286},
      pages        = {13},
      year         = {2023},
      note         = {CC BY},
      abstract     = {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.},
      keywords     = {Mice / Humans / Animals / Alzheimer Disease: drug therapy /
                      Amyloid Precursor Protein Secretases / Cytokine Receptor
                      gp130: therapeutic use / Aspartic Acid Endopeptidases /
                      Interleukin-6 / Nerve Tissue Proteins / IL-6 receptor
                      subunit beta (Other) / IL-6R (Other) / Secretase (Other) /
                      Shedding (Other) / Trans-signaling (Other) / VCAM1 (Other) /
                      Amyloid Precursor Protein Secretases (NLM Chemicals) /
                      Cytokine Receptor gp130 (NLM Chemicals) / Aspartic Acid
                      Endopeptidases (NLM Chemicals) / Interleukin-6 (NLM
                      Chemicals) / BACE1 protein, human (NLM Chemicals) / Sez6
                      protein, mouse (NLM Chemicals) / Nerve Tissue Proteins (NLM
                      Chemicals) / Bace1 protein, mouse (NLM Chemicals)},
      cin          = {AG Lichtenthaler},
      ddc          = {570},
      cid          = {I:(DE-2719)1110006},
      pnm          = {352 - Disease Mechanisms (POF4-352) / DFG project 390857198
                      - EXC 2145: Munich Cluster for Systems Neurology (SyNergy)
                      (390857198)},
      pid          = {G:(DE-HGF)POF4-352 / G:(GEPRIS)390857198},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9942414},
      pubmed       = {pmid:36810097},
      doi          = {10.1186/s13024-023-00596-6},
      url          = {https://pub.dzne.de/record/255485},
}