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Published year: 20241
Author: Regina Feederle1
The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.

Abstract (Expand)

The beta-secretase 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, non-human 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 a safer prevention of Alzheimer's disease.

Authors: A. Schmidt, B. Hrupka, F. van Bebber, S. Sunil Kumar, X. Feng, S. K. Tschirner, M. Assfalg, S. A. Muller, L. S. Hilger, L. I. Hofmann, M. Pigoni, G. Jocher, I. Voytyuk, E. L. Self, M. Ito, K. Hyakkoku, A. Yoshimura, N. Horiguchi, R. Feederle, B. De Strooper, S. Schulte-Merker, E. Lammert, D. Moechars, B. Schmid, S. F. Lichtenthaler

Date Published: 18th Jun 2024

Publication Type: Journal

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