The Beta secretase BACE1 drives fibroblasts activation in Systemic Sclerosis through the APP/Beta-catenin/Notch signalling axis

Background The beta-amyloid precursor protein cleaving enzyme 1 (BACE1) is well known for its role in the development of Alzheimers disease via the generation of beta-amyloid. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic inflammatory diseases, including type 2 diabetes and cardiovascular disease. However, to date there has been no studies looking into the role of BACE1 in the autoimmune condition Systemic Sclerosis (SSc). The aim of this study was to investigate the role of BACE1 in SSc tissue fibrosis. Methods Patient fibroblasts were obtained from full thickness forearm skin biopsies from healthy and early diffuse SSc patients. BACE1 was inhibited with the small molecule inhibitors M-3 and AZD3839 and siRNA specific to BACE1. Morphogen signalling was activated with recombinant TGF-B, Wnt-3a or the smoothened agonist SAG. Xenotransplant mouse model using patient pDC was used to interrogate in vivo expression of BACE1 in fibrosis. Results Here we show that BACE1 protein levels are elevated in SSc patient skin biopsies, as well as dermal fibroblasts and in mouse skin during fibrosis. Inhibition of BACE1 with small molecule inhibitors or siRNA blocked SSc and morphogen mediated fibroblast pro-fibrotic activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on the B-catenin and Notch signalling pathway activation. Conclusions The ability of BACE1 to regulate SSc fibroblast activation reveals an exciting new therapeutic target in SSc. Several BACE1 inhibitors, including AZD3839, have been shown to be safe in clinical trials for Alzheimers disease. ### Competing Interest Statement The authors have declared no competing interest.