Summary β‐site amyloid precursor protein cleaving enzyme‐1 (BACE1) research has historically focused on its actions as the β‐secretase responsible for the production of β‐amyloid beta, observed in Alzheimer's disease. Although the greatest expression of BACE1 is found in the brain, BACE1 mRNA and protein is also found in many cell types including pancreatic β‐cells, adipocytes, hepatocytes, and vascular cells. Pathologically elevated BACE1 expression in these cells has been implicated in the development of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease. In this review, we examine key questions surrounding the BACE1 literature, including how is BACE1 regulated and how dysregulation may occur in disease, and understand how BACE1 regulates metabolism via cleavage of a myriad of substrates. The phenotype of the BACE1 knockout mice models, including reduced weight gain, increased energy expenditure, and enhanced leptin signaling, proposes a physiological role of BACE1 in regulating energy metabolism and homeostasis. Taken together with the weight loss observed with BACE1 inhibitors in clinical trials, these data highlight a novel role for BACE1 in regulation of metabolic physiology. Finally, this review aims to examine the possibility that BACE1 inhibitors could provide a innovative treatment for obesity and its comorbidities.

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The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer’s disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aβ) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have successfully improved AD pathogenesis, despite effectively lowering Aβ concentrations. This can, in part, be attributed to an incomplete understanding of BACE1, including its physiological functions and substrate specificity. We propose that BACE1 has additional important physiological functions, mediated through substrates still to be identified. Thus, to address this, we computationally analysed a list of 533 BACE1 dependent proteins, identified from the literature, for potential BACE1 substrates, and compared them against proteins differentially expressed in AD. We identified 15 novel BACE1 substrates that were specifically altered in AD. To confirm our analysis, we validated Protein tyrosine phosphatase receptor type D (PTPRD) and Netrin receptor DCC (DCC) using Western blotting. These findings shed light on the BACE1 inhibitor failings and could enable the design of substrate-specific inhibitors to target alternative BACE1 substrates. Furthermore, it gives us a greater understanding of the roles of BACE1 and its dysfunction in AD.

The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of 2 extracellular α-subunits and 2 transmembrane β-subunits. IR α/β and IGF-1R α/β hemi-receptors can heterodimerize to form hybrids composed of one IR α/β and one IGF-1R α/β. Widely distributed in mammalian tissues, in contrast to IR and IGF-1R the physiological function of hybrids is unclear. To identify tool compounds that inhibit hybrid formation we performed a high-throughput small molecule screen based on a homology model of hybrid structure. Our studies unveil a first in class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells (HUVECs) with no effect on IR or IGF-1R. Downstream of IR and IGF-1R our small molecule led to reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, an increase in phosphorylation of its downstream target Akt and enhanced insulin and shear-induced phosphorylation of Akt. We show that hybrids have a role in human EC physiology distinct from IR and IGF1R.

BackgroundThe beta-amyloid precursor protein cleaving enzyme 1 (BACE1) is well known for its role in the development of Alzheimer’s disease via the generation of β-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).ObjectivesThe aim of this study was to assess the expression profile of BACE1 in SSc patient samples and investigate the effects of BACE1 inhibitors and siRNA on SSc fibroblast activation.MethodsPatient fibroblasts were obtained from full thickness forearm skin biopsies from healthy and early diffuse SSc patients. BACE1 was inhibited with 2 specific small molecule inhibitors and siRNA specific to BACE1. Morphogen signalling was activated with recombinant TGF-β, Wnt-3a or the smoothened agonist SAG. A xenotransplant bleomycin mouse model using patient pDC was used to interrogatein vivoexpression of BACE1 in fibrosis.ResultsHere we show that BACE1 protein levels are elevated in SSc patient skin biopsies. In particular BACE1 was increased in the fibroblasts and endothelial cells of the SSc skin. BACE1 was elevated in isolated dermal fibroblasts grown in culture (2.3 fold increase, N=4). BACE1 protein levels were elevated in the bleomycin skin fibrosis model. Interestingly BACE1 mRNA levels were unaffected in cultured SSc fibroblasts, suggesting a post-translational modification led to the elevated protein levels.Inhibition of BACE1 with small molecule inhibitors (that have been proven safe in phase 1 clinical trials for Alzheimer’s) or siRNA blocked pro-fibrotic gene (alpha SMA, Collagen Type 1 and CTGF) expression in SSc fibroblasts. In addition overexpression of BACE1 in healthy fibroblasts resulted in myofibroblast activation (2-fold increase in alpha SMA protein expression). Interestingly overexpression of a BACE1 mutant construct which disrupts the secretase activity of the protein, was unable to induce fibroblast activation.Disruption of BACE1 (with both the inhibitors and siRNA) blocked morphogen mediated fibroblasts activation. The BACE1 inhibitors and siRNA blocked TGF-β, Wnt-3a and Hedgehog mediated alpha-SMA expression in healthy fibroblasts. Furthermore, we show that BACE1 regulation of dermal fibroblast activation was dependent on the β-catenin and Notch signalling pathways. BACE1 ability to regulate non-canonical Wnt receptors led to elevated β-catenin expression which in turn activated the Notch signalling pathway.ConclusionThis is the first evidence that BACE1 and in particular its secretase activity, plays a role in SSc and fibrosis in general. The ability of BACE1 to regulate SSc fibroblast activation reveals an exciting new therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in phase 1 clinical trials for Alzheimer’s disease. Future work includes investigating the role of BACE1 in vascular/endothelial cell dysfunction in SSc.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.