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Schmidt, A.* ; Hrupka, B.J.* ; van Bebber, F.* ; Sunil Kumar, S.* ; Feng, X.* ; Tschirner, S.K.* ; Aßfalg, M.* ; Müller, S.A.* ; Hilger, L.S.* ; Hofmann, L.I.* ; Pigoni, M.* ; Jocher, G.* ; Voytyuk, I.* ; Self, E.L.* ; Ito, M.* ; Hyakkoku, K.* ; Yoshimura, A.* ; Horiguchi, N.* ; Feederle, R. ; de Strooper, B.* ; Schulte-Merker, S.* ; Lammert, E.* ; Moechars, D.* ; Schmid, B.* ; Lichtenthaler, S.F.*

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

J. Clin. Invest. 134:e170550 (2024)

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	Open Access Gold (Paid Option)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Aging ; Alzheimer Disease ; Drug Therapy; Amyloid Precursor Protein; Growth-factor Receptor-3; Beta-site; Computational Platform; Vascular Development; Proteomic Analysis; Randomized-trial; Verubecestat; Morphogenesis; Enrichment

ISSN (print) / ISBN 0021-9738

e-ISSN 1558-8238

Journal Journal of Clinical Investigation

Quellenangaben Volume: 134, Issue: 16, Article Number: e170550

Publisher American Society of Clinical Investigation

Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Monoclonal Antibodies (CF-MAB)

Grants Helmholtz Association
CiM-IMPRS graduate school
Federal Ministry of Education and Research
Cure Alzheimer's Fund
Institute for the Promotion of Innovation by Science and Technology in Flanders
Alzheimer's Association
Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology
CRC 1348 (DFG)
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)