AI Article Synopsis
- BACE1 is a key target for Alzheimer's treatment, but existing drugs also affect BACE2, a related protease with unclear functions.
- Researchers found that BACE2 is responsible for shedding VEGFR3, a receptor linked to lymphatic growth; blocking BACE2 increases the receptor levels and its signaling in lymphatic cells.
- This study highlights sVEGFR3 as a valuable blood marker for BACE2 activity, paving the way for safer Alzheimer's drugs that selectively inhibit BACE1.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324312 | PMC |
| http://dx.doi.org/10.1172/JCI170550 | DOI Listing |
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