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

Aging Alzheimer disease Drug therapy

Journal

The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877

Informations de publication

Date de publication:
18 Jun 2024
Historique:
medline: 18 6 2024
pubmed: 18 6 2024
entrez: 18 6 2024
Statut: aheadofprint

Résumé

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.

Identifiants

pubmed: 38888964
pii: 170550
doi: 10.1172/JCI170550
doi:
pii:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Andree Schmidt (A)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Brian Hrupka (B)

Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium.

Frauke van Bebber (F)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Sanjay Sunil Kumar (S)

Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany.

Xiao Feng (X)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Sarah K Tschirner (SK)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Marlene Aßfalg (M)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Stephan A Müller (SA)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Laura Sophie Hilger (LS)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Laura I Hofmann (LI)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Martina Pigoni (M)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Georg Jocher (G)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Iryna Voytyuk (I)

Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

Emily L Self (EL)

MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.

Mana Ito (M)

Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan.

Kana Hyakkoku (K)

Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan.

Akimasa Yoshimura (A)

Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan.

Naotaka Horiguchi (N)

Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan.

Regina Feederle (R)

Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Bart De Strooper (B)

Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.

Stefan Schulte-Merker (S)

Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany.

Eckhard Lammert (E)

Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany.

Dieder Moechars (D)

Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium.

Bettina Schmid (B)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Stefan F Lichtenthaler (SF)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Classifications MeSH