2. Academic Validation
  3. The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling

The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling

  • J Clin Invest. 2024 Jun 18;134(16):e170550. doi: 10.1172/JCI170550.
Andree Schmidt 1 2 3 4,  Brian Hrupka 5,  Frauke van Bebber 1,  Sanjay Sunil Kumar 6,  Xiao Feng 1 2,  Sarah K Tschirner 1 2,  Marlene Aßfalg 1 2,  Stephan A Müller 1 2,  Laura Sophie Hilger 1 7 8,  Laura I Hofmann 1 2,  Martina Pigoni 1 2 3,  Georg Jocher 1 2,  Iryna Voytyuk 9 10,  Emily L Self 11,  Mana Ito 12,  Kana Hyakkoku 12,  Akimasa Yoshimura 12,  Naotaka Horiguchi 12,  Regina Feederle 1 13 14,  Bart De Strooper 9 10 15,  Stefan Schulte-Merker 6,  Eckhard Lammert 7 16 17,  Dieder Moechars 5,  Bettina Schmid 1,  Stefan F Lichtenthaler 1 2 14
Affiliations

Affiliations

  • 1 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 2 Neuroproteomics, School of Medicine and Health, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
  • 3 Graduate School of Systemic Neurosciences (GSN), Ludwig Maximilian University (LMU) Munich, Munich, Germany.
  • 4 Evotec München, Neuried, Germany.
  • 5 Discovery Neuroscience, Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, Belgium.
  • 6 Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WU Münster, Münster, Germany.
  • 7 Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, and.
  • 8 International Research Training Group (IRTG1902), Heinrich-Heine-University, Düsseldorf, Germany.
  • 9 Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.
  • 10 Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium.
  • 11 MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.
  • 12 Shionogi & Co., Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Toyonaka-shi, Osaka, Japan.
  • 13 Core Facility Monoclonal Antibodies, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • 14 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 15 UK Dementia Research Institute (UKDRI) at University College London, London, United Kingdom.
  • 16 Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
  • 17 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
PMID: 38888964 DOI: 10.1172/JCI170550
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

Aging; Alzheimer disease; Drug therapy.

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