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@ARTICLE{Tschirner:280289,
      author       = {Tschirner, Sarah K and Zuchero, Y Joy Yu and Getz, Jennifer
                      A and Müller, Stephan A and Nalbach, Karsten and Kennedy,
                      Matthew E and Lewcock, Joseph W and Lichtenthaler, Stefan F},
      title        = {{S}oluble {VCAM}-1 {M}ay {S}erve as a {P}harmacodynamic
                      {CSF} {M}arker to {M}onitor {BACE}2 {A}ctivity in
                      {N}on-{H}uman {P}rimates.},
      journal      = {Molecular $\&$ cellular proteomics},
      volume       = {24},
      number       = {7},
      issn         = {1535-9476},
      address      = {Bethesda, Md.},
      publisher    = {The American Society for Biochemistry and Molecular
                      Biology},
      reportid     = {DZNE-2025-00944},
      pages        = {101012},
      year         = {2025},
      abstract     = {The β-secretase β-site APP cleaving enzyme 1 (BACE1) is a
                      major drug target for Alzheimer's disease (AD). Clinically
                      tested BACE1 inhibitors induced unexpected cognitive side
                      effects that may stem from their cross-inhibition of the
                      homologous protease BACE2. Yet, little is known about BACE2
                      functions and substrates in vivo, and no biomarker is
                      available to monitor the extent of BACE2 inhibition in vivo,
                      particularly in cerebrospinal fluid (CSF). To identify a
                      potential CSF biomarker for monitoring BACE2 activity, we
                      analyzed the CSF proteome changes in non-human primates
                      after treatment with a BACE1-selective inhibitor (a
                      brain-targeted monoclonal antibody) in comparison to
                      verubecestat, a clinically tested small-molecule drug
                      inhibiting both BACE1 and BACE2. Acute treatment with either
                      the antibody or verubecestat similarly reduced CSF abundance
                      of the cleavage products of several known BACE1 substrates,
                      including SEZ6, gp130, and CACHD1, demonstrating similar
                      target engagement in vivo. One CSF protein, vascular cell
                      adhesion protein 1 (VCAM-1), was only reduced upon
                      inhibition with verubecestat, but not upon BACE1-selective
                      inhibition with the antibody. We conclude that VCAM-1 is a
                      promising biomarker candidate for monitoring BACE2
                      inhibition in CSF, which is instrumental for the development
                      of BACE1-selective inhibitors for the prevention of AD.},
      keywords     = {Animals / Amyloid Precursor Protein Secretases: antagonists
                      $\&$ inhibitors / Amyloid Precursor Protein Secretases:
                      metabolism / Amyloid Precursor Protein Secretases:
                      cerebrospinal fluid / Aspartic Acid Endopeptidases:
                      antagonists $\&$ inhibitors / Aspartic Acid Endopeptidases:
                      metabolism / Aspartic Acid Endopeptidases: cerebrospinal
                      fluid / Biomarkers: cerebrospinal fluid / Vascular Cell
                      Adhesion Molecule-1: cerebrospinal fluid / Antibodies,
                      Monoclonal: pharmacology / Humans / Male / Amyloid Precursor
                      Protein Secretases (NLM Chemicals) / Aspartic Acid
                      Endopeptidases (NLM Chemicals) / Biomarkers (NLM Chemicals)
                      / Vascular Cell Adhesion Molecule-1 (NLM Chemicals) /
                      Antibodies, Monoclonal (NLM Chemicals)},
      cin          = {AG Lichtenthaler},
      ddc          = {610},
      cid          = {I:(DE-2719)1110006},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40480341},
      pmc          = {pmc:PMC12280488},
      doi          = {10.1016/j.mcpro.2025.101012},
      url          = {https://pub.dzne.de/record/280289},
}