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

Schmidt, Andree; Hrupka, Brian; Bebber, Frauke van; Sunil Kumar, Sanjay; Feng, Xiaoqi; Tschirner, Sarah K.; Aßfalg, Marlene; Müller, Stephan A.; Hilger, Laura Sophie; Hofmann, Laura I.; Pigoni, Martina; Jocher, Georg ; Voytyuk, Iryna ; Self, Emily L.; Ito, Mana; Hyakkoku, Kana; Yoshimura, Akimasa; Horiguchi, Naotaka; Feederle, Regina; Strooper, Bart De; Schulte-Merker, Stefan; Lammert, Eckhard; Moechars, Dieder; Schmid, Bettina und Lichtenthaler, Stefan F. (2024): The Alzheimer’s disease–linked protease BACE2 cleaves VEGFR3 and modulates its signaling. In: Journal of Clinical Investigation, Vol. 134, No. 16, e170550

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.

• Item Type: Journal article
• Faculties: Biology; Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Institute for Stroke and Dementia Research (ISD)
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1558-8238
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198