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@ARTICLE{Schmidt:271340,
      author       = {Schmidt, Andree and Hrupka, Brian and van Bebber, Frauke
                      and Sunil Kumar, Sanjay and Feng, Xiao and Tschirner, Sarah
                      K and Aßfalg, Marlene and Müller, Stephan A and Hilger,
                      Laura Sophie and Hofmann, Laura I and Pigoni, Martina and
                      Jocher, Georg and Voytyuk, Iryna and Self, Emily L and Ito,
                      Mana and Hyakkoku, Kana and Yoshimura, Akimasa and
                      Horiguchi, Naotaka and Feederle, Regina and De Strooper,
                      Bart and Schulte-Merker, Stefan and Lammert, Eckhard and
                      Moechars, Dieder and Schmid, Bettina and Lichtenthaler,
                      Stefan F},
      title        = {{T}he {A}lzheimer's disease-linked protease {BACE}2 cleaves
                      {VEGFR}3 and modulates its signaling.},
      journal      = {The journal of clinical investigation},
      volume       = {134},
      number       = {16},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DZNE-2024-01041},
      pages        = {e170550},
      year         = {2024},
      abstract     = {The β-secretase β-site APP cleaving enzyme (BACE1) is a
                      central drug target for Alzheimer's disease. Clinically
                      tested, BACE1-directed inhibitors also block the homologous
                      protease BACE2. Yet little is known about physiological
                      BACE2 substrates and functions in vivo. Here, we identify
                      BACE2 as the protease shedding the lymphangiogenic vascular
                      endothelial growth factor receptor 3 (VEGFR3). Inactivation
                      of BACE2, but not BACE1, inhibited shedding of VEGFR3 from
                      primary human lymphatic endothelial cells (LECs) and reduced
                      release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain
                      into the blood of mice, nonhuman primates, and humans.
                      Functionally, BACE2 inactivation increased full-length
                      VEGFR3 and enhanced VEGFR3 signaling in LECs and also in
                      vivo in zebrafish, where enhanced migration of LECs was
                      observed. Thus, this study identifies BACE2 as a modulator
                      of lymphangiogenic VEGFR3 signaling and demonstrates the
                      utility of sVEGFR3 as a pharmacodynamic plasma marker for
                      BACE2 activity in vivo, a prerequisite for developing
                      BACE1-selective inhibitors for safer prevention of
                      Alzheimer's disease.},
      keywords     = {Amyloid Precursor Protein Secretases: metabolism / Amyloid
                      Precursor Protein Secretases: genetics / Amyloid Precursor
                      Protein Secretases: antagonists $\&$ inhibitors / Animals /
                      Aspartic Acid Endopeptidases: metabolism / Aspartic Acid
                      Endopeptidases: genetics / Aspartic Acid Endopeptidases:
                      antagonists $\&$ inhibitors / Humans / Mice / Vascular
                      Endothelial Growth Factor Receptor-3: metabolism / Vascular
                      Endothelial Growth Factor Receptor-3: genetics / Signal
                      Transduction / Zebrafish: metabolism / Zebrafish: genetics /
                      Alzheimer Disease: metabolism / Alzheimer Disease: genetics
                      / Alzheimer Disease: pathology / Alzheimer Disease:
                      enzymology / Endothelial Cells: metabolism / Endothelial
                      Cells: enzymology / Endothelial Cells: pathology / Zebrafish
                      Proteins: genetics / Zebrafish Proteins: metabolism / Aging
                      (Other) / Alzheimer disease (Other) / Drug therapy (Other) /
                      Amyloid Precursor Protein Secretases (NLM Chemicals) /
                      Aspartic Acid Endopeptidases (NLM Chemicals) / Vascular
                      Endothelial Growth Factor Receptor-3 (NLM Chemicals) / BACE2
                      protein, human (NLM Chemicals) / FLT4 protein, human (NLM
                      Chemicals) / Bace2 protein, mouse (NLM Chemicals) /
                      Zebrafish Proteins (NLM Chemicals) / BACE1 protein, human
                      (NLM Chemicals)},
      cin          = {AG Lichtenthaler / AG Schmid München / AG Feederle},
      ddc          = {610},
      cid          = {I:(DE-2719)1110006 / I:(DE-2719)1140002 /
                      I:(DE-2719)1140004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38888964},
      pmc          = {pmc:PMC11324312},
      doi          = {10.1172/JCI170550},
      url          = {https://pub.dzne.de/record/271340},
}