Schmidt, Andree;
Hrupka, Brian;
van Bebber, Frauke;
Sunil Kumar, Sanjay;
Feng, Xiao;
Tschirner, Sarah K;
Aßfalg, Marlene;
... Lichtenthaler, Stefan F; + view all
(2024)
The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
The Journal of Clinical Investigation
, Article e170550. 10.1172/JCI170550.
(In press).
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Abstract
The β-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.
| Type: | Article |
|---|---|
| Title: | The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/JCI170550 |
| Publisher version: | http://dx.doi.org/10.1172/jci170550 |
| Language: | English |
| Additional information: | Copyright © 2024, Schmidt et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Aging, Alzheimer disease, Drug therapy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10193806 |
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