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.
摘要：
β位点淀粉样前体蛋白裂解酶1（BACE1）是阿尔茨海默病（AD）的广泛研究的治疗靶点，由于其在神经毒性淀粉样β（Aβ）肽的产生中的作用。然而,尽管许多BACE1抑制剂进入临床试验，没有一个成功地改善AD的发病机制，尽管有效降低Aβ浓度。这个可以,在某种程度上,归因于对BACE1的不完全理解，包括其生理功能和底物特异性。我们建议BACE1具有其他重要的生理功能，通过底物介导仍有待鉴定。因此，为了解决这个问题，我们计算分析了533个BACE1依赖蛋白，从文献中确定，对于潜在的BACE1底物，并将它们与在AD中差异表达的蛋白质进行比较。我们鉴定了15种在AD中特异性改变的新型BACE1底物。为了证实我们的分析,我们使用蛋白质印迹法验证了蛋白酪氨酸磷酸酶受体D型(PTPRD)和Netrin受体DCC(DCC).这些发现揭示了BACE1抑制剂的失败，并且可以设计针对替代BACE1底物的底物特异性抑制剂。此外，它使我们对BACE1及其功能障碍在AD中的作用有了更深入的了解。
