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001     271340
005     20240901004633.0
024 7 _ |a 10.1172/JCI170550
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024 7 _ |a pmc:PMC11324312
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024 7 _ |a 0021-9738
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024 7 _ |a 1558-8238
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037 _ _ |a DZNE-2024-01041
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Schmidt, Andree
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245 _ _ |a The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
260 _ _ |a Ann Arbor, Mich.
|c 2024
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336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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650 _ 7 |a Aging
|2 Other
650 _ 7 |a Alzheimer disease
|2 Other
650 _ 7 |a Drug therapy
|2 Other
650 _ 7 |a Amyloid Precursor Protein Secretases
|0 EC 3.4.-
|2 NLM Chemicals
650 _ 7 |a Aspartic Acid Endopeptidases
|0 EC 3.4.23.-
|2 NLM Chemicals
650 _ 7 |a Vascular Endothelial Growth Factor Receptor-3
|0 EC 2.7.10.1
|2 NLM Chemicals
650 _ 7 |a BACE2 protein, human
|0 EC 3.4.23.45
|2 NLM Chemicals
650 _ 7 |a FLT4 protein, human
|0 EC 2.7.10.1
|2 NLM Chemicals
650 _ 7 |a Bace2 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Zebrafish Proteins
|2 NLM Chemicals
650 _ 7 |a BACE1 protein, human
|0 EC 3.4.23.46
|2 NLM Chemicals
650 _ 2 |a Amyloid Precursor Protein Secretases: metabolism
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: genetics
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: metabolism
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: genetics
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Vascular Endothelial Growth Factor Receptor-3: metabolism
|2 MeSH
650 _ 2 |a Vascular Endothelial Growth Factor Receptor-3: genetics
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Zebrafish: metabolism
|2 MeSH
650 _ 2 |a Zebrafish: genetics
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Alzheimer Disease: enzymology
|2 MeSH
650 _ 2 |a Endothelial Cells: metabolism
|2 MeSH
650 _ 2 |a Endothelial Cells: enzymology
|2 MeSH
650 _ 2 |a Endothelial Cells: pathology
|2 MeSH
650 _ 2 |a Zebrafish Proteins: genetics
|2 MeSH
650 _ 2 |a Zebrafish Proteins: metabolism
|2 MeSH
700 1 _ |a Hrupka, Brian
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700 1 _ |a van Bebber, Frauke
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700 1 _ |a Sunil Kumar, Sanjay
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700 1 _ |a Feng, Xiao
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700 1 _ |a Tschirner, Sarah K
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700 1 _ |a Aßfalg, Marlene
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700 1 _ |a Müller, Stephan A
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700 1 _ |a Hilger, Laura Sophie
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700 1 _ |a Hofmann, Laura I
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700 1 _ |a Pigoni, Martina
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700 1 _ |a Jocher, Georg
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700 1 _ |a Voytyuk, Iryna
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700 1 _ |a Self, Emily L
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700 1 _ |a Ito, Mana
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700 1 _ |a Hyakkoku, Kana
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700 1 _ |a Yoshimura, Akimasa
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700 1 _ |a Horiguchi, Naotaka
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700 1 _ |a Feederle, Regina
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700 1 _ |a De Strooper, Bart
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700 1 _ |a Schulte-Merker, Stefan
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700 1 _ |a Lammert, Eckhard
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700 1 _ |a Moechars, Dieder
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700 1 _ |a Schmid, Bettina
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700 1 _ |a Lichtenthaler, Stefan F
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773 _ _ |a 10.1172/JCI170550
|g Vol. 134, no. 16, p. e170550
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|t The journal of clinical investigation
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