Journal Article

The Alzheimer’s disease–linked protease BACE2 cleaves VEGFR3 and modulates its signaling

Hofmann, Laura I., Tschirner, Sarah K., De Strooper, Bart, Ito, Mana, Lammert, Eckhard, Yoshimura, Akimasa, Moechars, Dieder, Horiguchi, Naotaka, Self, Emily L., Hilger, Laura Sophie, Aßfalg, Marlene, Müller, Stephan A., Lichtenthaler, Stefan F., Pigoni, Martina, Hyakkoku, Kana, van Bebber, Frauke, Jocher, Georg, Schmid, Bettina, Schulte-Merker, Stefan, Feng, Xiao, Feederle, Regina, Sunil Kumar, Sanjay, Voytyuk, Iryna, Schmidt, Andree, Hrupka, Brian

2024

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Aging / Alzheimer Disease - enzymology / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amino acids / Amyloid Precursor Protein Secretases - antagonists & inhibitors / Amyloid Precursor Protein Secretases - genetics / Amyloid Precursor Protein Secretases - metabolism / Animals / Aspartic Acid Endopeptidases - antagonists & inhibitors / Aspartic Acid Endopeptidases - genetics / Aspartic Acid Endopeptidases - metabolism / Belgium / Computer software industry / Diseases / Drug dosages / Endothelial cells / Endothelial Cells - enzymology / Endothelial Cells - metabolism / Endothelial Cells - pathology / Enzyme inhibitors / Enzymes / Germany / Growth / Growth factor receptors / Health aspects / Humans / Immunoassay / Kinases / Lymphatics / Mice / Neurodegenerative diseases / Peptides / Pharmacodynamics / Pharmacology, Experimental / Physiological aspects / Plasma / Proteases / Proteinase / Proteinase inhibitors / Proteins / Proteomics / Scientific equipment and supplies industry / Secretase / Signal Transduction / Testing / Therapeutic targets / United States / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-3 - genetics / Vascular Endothelial Growth Factor Receptor-3 - metabolism / Vascular endothelial growth factor receptors / Zebrafish - genetics / Zebrafish - metabolism / Zebrafish Proteins - genetics / Zebrafish Proteins - metabolism / β-Site APP-cleaving enzyme 1 / β-Site APP-cleaving enzyme 2