Wasson, C.W., De Lorenzis, E., Clavane, E.M. et al. (14 more authors) (2024) The β-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/β-Catenin/Notch Signaling Axis. Journal of Investigative Dermatology, 144 (10). pp. 2197-2210. ISSN 0022-202X
Abstract
The beta-amyloid precursor protein cleaving enzyme 1 (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 SSc patient skin. Inhibition of BACE1 with small molecule inhibitors or siRNA blocked SSc and fibrotic stimuli mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on β-catenin and Notch signalling. The Neurotropic factor BDNF negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from SSc patients show higher Aβ and lower BDNF levels compared to 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Fibrosis, Wnt, Notch, Autoimmunity |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number BBSRC (Biotechnology & Biological Sciences Research Council) BB/V014358/1 British Heart Foundation FS/13/38/33659 |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Apr 2024 09:40 |
Last Modified: | 04 Oct 2024 10:20 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jid.2024.03.024 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:210950 |