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
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