Journal article
The f3-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/β-Catenin/Notch β-Catenin/Notch Signaling Axis
Journal of investigative dermatology, v 144(10)
01 Oct 2024
PMID: 38570030
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
BACE1 is well-known for its role in the development of Alzheimer's disease. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic diseases. The aim of this study was to investigate the role of BACE1 in the autoimmune disease systemic sclerosis (SSc). BACE1 protein levels were elevated in the skin of patients with SSc. Inhibition of BACE1 with small-molecule inhibitors or small interfering RNA blocked SSc and fibrotic stimuli-mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on beta-catenin and Notch signaling. The neurotropic factor brain-derived neurotrophic factor negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from patients with SSc show higher beta-amyloid and lower brain-derived neurotrophic factor levels than healthy controls. The ability of BACE1 to regulate SSc fibroblast activation reveals a therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer's disease and could be repurposed to ameliorate fibrosis progression.
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Details
- Title
- The f3-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/β-Catenin/Notch β-Catenin/Notch Signaling Axis
- Creators
- Christopher W. Wasson - University of LeedsEnrico De Lorenzis - Università Cattolica del Sacro CuoreEva M. Clavane - University of LeedsRebecca L. Ross - University of LeedsKieran A. Walker - University of LeedsBegona Caballero-Ruiz - University of LeedsCristina Antinozzi - Foro Italico University of RomeRebecca Wells - University of LeedsGemma Migneco - Drexel UniversityJane M. Y. Brown - University of LeedsSamuel J. Turvey - University of LeedsKatie J. Simmons - University of LeedsNatalia A. Riobo-Del Galdo - University of LeedsLuigi Di Luigi - Foro Italico University of RomeClive S. Mckimmie - University of LeedsFrancesco Del Galdo - University of LeedsPaul J. Meakin - University of Leeds
- Publication Details
- Journal of investigative dermatology, v 144(10)
- Publisher
- Elsevier
- Number of pages
- 18
- Grant note
- FS/4yPhD/F/20/34130; FS/18/38/33659 / British Heart Foundation BB/V014358/1 / Biotechnology AMP; Biological Sciences Research Council; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC) Susan Cheney Scleroderma fellowship Medical Research Council Discovery Medicine North Doctoral Training Partnership studentship National Institute for Health Research Leeds Biomedical Research Centre
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001319623400001
- Other Identifier
- 991022202489404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Dermatology