%0 Journal Article
%A Schmidt, Andree
%A Hrupka, Brian
%A van Bebber, Frauke
%A Sunil Kumar, Sanjay
%A Feng, Xiao
%A Tschirner, Sarah K
%A Aßfalg, Marlene
%A Müller, Stephan A
%A Hilger, Laura Sophie
%A Hofmann, Laura I
%A Pigoni, Martina
%A Jocher, Georg
%A Voytyuk, Iryna
%A Self, Emily L
%A Ito, Mana
%A Hyakkoku, Kana
%A Yoshimura, Akimasa
%A Horiguchi, Naotaka
%A Feederle, Regina
%A De Strooper, Bart
%A Schulte-Merker, Stefan
%A Lammert, Eckhard
%A Moechars, Dieder
%A Schmid, Bettina
%A Lichtenthaler, Stefan F
%T The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
%J The journal of clinical investigation
%V 134
%N 16
%@ 0021-9738
%C Ann Arbor, Mich.
%I ASCJ
%M DZNE-2024-01041
%P e170550
%D 2024
%X 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.
%K Amyloid Precursor Protein Secretases: metabolism
%K Amyloid Precursor Protein Secretases: genetics
%K Amyloid Precursor Protein Secretases: antagonists & inhibitors
%K Animals
%K Aspartic Acid Endopeptidases: metabolism
%K Aspartic Acid Endopeptidases: genetics
%K Aspartic Acid Endopeptidases: antagonists & inhibitors
%K Humans
%K Mice
%K Vascular Endothelial Growth Factor Receptor-3: metabolism
%K Vascular Endothelial Growth Factor Receptor-3: genetics
%K Signal Transduction
%K Zebrafish: metabolism
%K Zebrafish: genetics
%K Alzheimer Disease: metabolism
%K Alzheimer Disease: genetics
%K Alzheimer Disease: pathology
%K Alzheimer Disease: enzymology
%K Endothelial Cells: metabolism
%K Endothelial Cells: enzymology
%K Endothelial Cells: pathology
%K Zebrafish Proteins: genetics
%K Zebrafish Proteins: metabolism
%K Aging (Other)
%K Alzheimer disease (Other)
%K Drug therapy (Other)
%K Amyloid Precursor Protein Secretases (NLM Chemicals)
%K Aspartic Acid Endopeptidases (NLM Chemicals)
%K Vascular Endothelial Growth Factor Receptor-3 (NLM Chemicals)
%K BACE2 protein, human (NLM Chemicals)
%K FLT4 protein, human (NLM Chemicals)
%K Bace2 protein, mouse (NLM Chemicals)
%K Zebrafish Proteins (NLM Chemicals)
%K BACE1 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38888964
%2 pmc:PMC11324312
%R 10.1172/JCI170550
%U https://pub.dzne.de/record/271340