Background/Purpose: Extensive work in the Alzheimer’s field has shown BACE1 plays an important role in amyloid beta processing. Additionally, there is evidence showing BACE1 regulating Notch signalling and disrupting angiogenesis in the context of Alzheimer’s. Given the known role of Notch signalling and disrupted angiogenesis in Systemic Sclerosis (SSc), in this study we investigated the role of BACE1 in the profibrotic phenotype of dermal fibroblasts from SSc skin.

Methods: Dermal fibroblasts were obtained from full thickness skin biopsies from early-diffuse cutaneous SSc patients. Protein was collected from the fibroblasts and BACE1 protein levels were assessed by western blot. SSc patient fibroblasts were treated with the BACE1 inhibitor M3.

Results: BACE1 protein levels were found to be expressed at significantly higher levels in SSc patient fibroblasts compared to healthy controls (1.9-Fold). Inhibition of BACE1 with the specific small molecule inhibitor led to reduced myofibroblast marker (Collagen type 1, alpha smooth muscle actin and CTGF) expression in SSc fibroblasts. Further analysis found inhibition of BACE1 could block the morphogen (TGF-b, Sonic hedgehog and Wnt-3a) mediated fibroblast activation. The BACE1 inhibitor reduced alpha smooth muscle actin expression in TGF-b stimulated fibroblasts by 50%, in sonic hedgehog stimulated cells by 65% and in Wnt-3a stimulated cells by 35%. Finally, treatment of SSc fibroblasts with the BACE1 small molecule inhibitor resulted in reduced expression of the active form of Notch1 and downstream targets Hes1 and GLI2, suggesting BACE1 contributes to SSc fibroblast phenotype through the activation of Notch signalling pathway.

Conclusion: We have identified a novel role for BACE1 in SSc myofibroblast activation through Notch1. This further strengthen the important role Notch signalling plays in SSc. Furthermore, this study highlights BACE1 as a potential novel antifibrotic target for therapeutic intervention which could be investigated with a number of BACE1 inhibitors currently in clinical trials for Alzheimer’s.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-beta-secretase-bace1-induces-systemic-sclerosis-ssc-fibroblast-activation-through-the-regulation-of-the-pro-fibrotic-notch-signalling-pathway/