1. The β-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/β-Catenin/Notch Signaling Axis.
- Author
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Wasson CW, De Lorenzis E, Clavane EM, Ross RL, Walker KA, Caballero-Ruiz B, Antinozzi C, Wells R, Migneco G, Brown JMY, Turvey SJ, Simmons KJ, Riobo-Del Galdo NA, Di Luigi L, McKimmie CS, Del Galdo F, and Meakin PJ
- Subjects
- Humans, Amyloid beta-Protein Precursor metabolism, Amyloid beta-Protein Precursor genetics, Cells, Cultured, Male, Skin pathology, Skin metabolism, Female, Amyloid Precursor Protein Secretases metabolism, Scleroderma, Systemic pathology, Scleroderma, Systemic metabolism, Fibroblasts metabolism, Signal Transduction, beta Catenin metabolism, Aspartic Acid Endopeptidases metabolism, Receptors, Notch metabolism
- 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 β-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 β-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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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