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Open Access | 10.1172/JCI170550
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
Find articles by Schmidt, A. in: JCI | PubMed | Google Scholar
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
Find articles by Feng, X. in: JCI | PubMed | Google Scholar
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
Find articles by Hilger, L. in: JCI | PubMed | Google Scholar
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
Find articles by Pigoni, M. in: JCI | PubMed | Google Scholar
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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Jocher, G.
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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Voytyuk, I.
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
Find articles by Self, E. in: JCI | PubMed | Google Scholar
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
Find articles by Ito, M. in: JCI | PubMed | Google Scholar
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
Find articles by Yoshimura, A. in: JCI | PubMed | Google Scholar
1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
2Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium
3Faculty of Medicine, Institute of Cardiovascular Organogenesis and Regeneration, WU Münster, Muenster, Germany
4Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
5MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom
6Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan
7Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
8Institute of Metabolic Physiology, Heinrich Heine University, Duesseldorf, Germany
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Lichtenthaler, S.
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Published June 18, 2024 - More info
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.