Journal Article

DZNE-2024-01041

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.

Schmidt, A. (First author)DZNE* ; Hrupka, B. ; van Bebber, F.DZNE* ; Sunil Kumar, S. ; Feng, X.DZNE* ; Tschirner, S. K.DZNE* ; Aßfalg, M.DZNE* ; Müller, S. A.DZNE* ; Hilger, L. S.DZNE* ; Hofmann, L. I.DZNE* ; Pigoni, M.DZNE* ; Jocher, G.DZNE* ; Voytyuk, I. ; Self, E. L. ; Ito, M. ; Hyakkoku, K. ; Yoshimura, A. ; Horiguchi, N. ; Feederle, R.DZNE* ; De Strooper, B. ; Schulte-Merker, S. ; Lammert, E. ; Moechars, D. ; Schmid, B.DZNE* ; Lichtenthaler, S. F. (Last author)DZNE*

2024
ASCJ Ann Arbor, Mich.

This record in other databases:    

Please use a persistent id in citations: doi:10.1172/JCI170550

Abstract: 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.

Keyword(s): Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Amyloid Precursor Protein Secretases: genetics (MeSH) ; Amyloid Precursor Protein Secretases: antagonists & inhibitors (MeSH) ; Animals (MeSH) ; Aspartic Acid Endopeptidases: metabolism (MeSH) ; Aspartic Acid Endopeptidases: genetics (MeSH) ; Aspartic Acid Endopeptidases: antagonists & inhibitors (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Vascular Endothelial Growth Factor Receptor-3: metabolism (MeSH) ; Vascular Endothelial Growth Factor Receptor-3: genetics (MeSH) ; Signal Transduction (MeSH) ; Zebrafish: metabolism (MeSH) ; Zebrafish: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: enzymology (MeSH) ; Endothelial Cells: metabolism (MeSH) ; Endothelial Cells: enzymology (MeSH) ; Endothelial Cells: pathology (MeSH) ; Zebrafish Proteins: genetics (MeSH) ; Zebrafish Proteins: metabolism (MeSH) ; Aging ; Alzheimer disease ; Drug therapy ; Amyloid Precursor Protein Secretases ; Aspartic Acid Endopeptidases ; Vascular Endothelial Growth Factor Receptor-3 ; BACE2 protein, human ; FLT4 protein, human ; Bace2 protein, mouse ; Zebrafish Proteins ; BACE1 protein, human

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)
2. Genetic Models of Neurodegeneration (AG Schmid München)
3. Antibody Production (AG Feederle)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Plasma proteomics of mice treated with BACE inhibitors
PRoteomics IDEntifications Database (2024)2024   Fulltext BibTeX | EndNote: XML, Text | RIS

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Plasma proteomics of BACE2 KO mice
PRoteomics IDEntifications Database (2024)2024   Fulltext BibTeX | EndNote: XML, Text | RIS

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Plasma proteomics of BACE1, 2, and double KO mice
PRoteomics IDEntifications Database (2024)2024   Fulltext BibTeX | EndNote: XML, Text | RIS

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