ArticleThe Journal of clinical investigation2024
The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- BACE2 tunes lipid uptake through lipid transporters shedding supporting cancer cell proliferation.Journal of experimental & clinical cancer research : CR · 2026Article
- Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.Proteomics · 2026Article
- Predictive Performance of a Serum sRAGE/sVEGFR-3 Dual-Biomarker Combination for Hypercoagulability Status in PediatricInternational journal of general medicine · 2026Article
- BACE2-Induced Aberrant Lymphatic Network Aggravates the Local Inflammation in Arteriovenous Fistulas With Hyperphosphatemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Expression and function of β-site amyloid precursor protein-cleaving enzyme 2 in vascular endothelium.American journal of physiology. Heart and circulatory physiology · 2025Article
- Zebrafish Models of Induced Lymphangiogenesis: Current Advancements and Therapeutic Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Proteolysis of TAM receptors in autoimmune diseases and cancer: what does it say to us?Cell death & disease · 2025Review
- It's good to know what to BACE the specificity of your inhibitors on.The Journal of clinical investigation · 2024Article
- miR-137: A therapeutic candidate or a key molecular regulator in Alzheimer's disease?Journal of Alzheimer's disease reportsReview
- Inactivation of BACE2 stimulates release of endothelin-1 from human brain microvascular endothelial cells.Journal of Alzheimer's disease reportsArticle
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Authors and funding
25 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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