PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study

Abstract

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.

Human cerebrospinal fluid contains diverse lipoprotein subspecies enriched in proteins implicated in central nervous system health

“…Another interesting clique contains neurexin 3 (NRXN3), amyloid precursor-like-protein 1 (APLP1), and plexin domain containing 2 (PLXDC2). All three of these proteins are known substrates for proteolytic processing by βsecretase 1 (46)(47)(48). Dysregulation of this process can result in production of neurotoxic amyloid beta (Aβ) peptides that form amyloid plaques associated with multiple neurodegenerative disorders.…”

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

“…The 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 (5). However, our recent findings have demonstrated a role for this enzyme in other chronic inflammatory diseases associated with vascular damage, including type 2 diabetes and cardiovascular disease (6,7). Several links exist implicating a role for BACE1 in SSc.…”