The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
J Clin Invest
; 134(16)2024 Jun 18.
Article
en En
| MEDLINE
| ID: mdl-38888964
ABSTRACT
The ß-secretase ß-site APP cleaving enzyme (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, nonhuman 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 safer prevention of Alzheimer's disease.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pez Cebra
/
Transducción de Señal
/
Ácido Aspártico Endopeptidasas
/
Receptor 3 de Factores de Crecimiento Endotelial Vascular
/
Secretasas de la Proteína Precursora del Amiloide
/
Enfermedad de Alzheimer
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania