TY  - JOUR
AU  - Schmidt, Andree
AU  - Hrupka, Brian
AU  - van Bebber, Frauke
AU  - Sunil Kumar, Sanjay
AU  - Feng, Xiao
AU  - Tschirner, Sarah K
AU  - Aßfalg, Marlene
AU  - Müller, Stephan A
AU  - Hilger, Laura Sophie
AU  - Hofmann, Laura I
AU  - Pigoni, Martina
AU  - Jocher, Georg
AU  - Voytyuk, Iryna
AU  - Self, Emily L
AU  - Ito, Mana
AU  - Hyakkoku, Kana
AU  - Yoshimura, Akimasa
AU  - Horiguchi, Naotaka
AU  - Feederle, Regina
AU  - De Strooper, Bart
AU  - Schulte-Merker, Stefan
AU  - Lammert, Eckhard
AU  - Moechars, Dieder
AU  - Schmid, Bettina
AU  - Lichtenthaler, Stefan F
TI  - The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
JO  - The journal of clinical investigation
VL  - 134
IS  - 16
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DZNE-2024-01041
SP  - e170550
PY  - 2024
AB  - The β-secretase β-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.
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid Precursor Protein Secretases: antagonists & inhibitors
KW  - Animals
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Aspartic Acid Endopeptidases: genetics
KW  - Aspartic Acid Endopeptidases: antagonists & inhibitors
KW  - Humans
KW  - Mice
KW  - Vascular Endothelial Growth Factor Receptor-3: metabolism
KW  - Vascular Endothelial Growth Factor Receptor-3: genetics
KW  - Signal Transduction
KW  - Zebrafish: metabolism
KW  - Zebrafish: genetics
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: enzymology
KW  - Endothelial Cells: metabolism
KW  - Endothelial Cells: enzymology
KW  - Endothelial Cells: pathology
KW  - Zebrafish Proteins: genetics
KW  - Zebrafish Proteins: metabolism
KW  - Aging (Other)
KW  - Alzheimer disease (Other)
KW  - Drug therapy (Other)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor Receptor-3 (NLM Chemicals)
KW  - BACE2 protein, human (NLM Chemicals)
KW  - FLT4 protein, human (NLM Chemicals)
KW  - Bace2 protein, mouse (NLM Chemicals)
KW  - Zebrafish Proteins (NLM Chemicals)
KW  - BACE1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38888964
C2  - pmc:PMC11324312
DO  - DOI:10.1172/JCI170550
UR  - https://pub.dzne.de/record/271340
ER  -