Department of Neuroscience, Room E4032, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-3401, USA.
CNS Drugs. 2019 Mar;33(3):251-263. doi: 10.1007/s40263-019-00613-7.
Alzheimer's disease (AD), the most common cause of age-dependent dementia, is one of the most significant healthcare problems worldwide. Aggravating this situation, drugs that are currently US Food and Drug Administration (FDA)-approved for AD treatment do not prevent or delay disease progression. Therefore, developing effective therapies for AD patients is of critical urgency. Human genetic and clinical studies over the past three decades have indicated that abnormal generation or accumulation of amyloid-β (Aβ) peptides is a likely culprit in AD pathogenesis. Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1) (memapsin 2, β-secretase, Asp 2 protease) and γ-secretase. Mice deficient in BACE1 show abrogated production of Aβ. Therefore, pharmacological inhibition of BACE1 is being intensively pursued as a therapeutic approach to treat AD patients. Recent setbacks in clinical trials with BACE1 inhibitors have highlighted the critical importance of understanding how to properly inhibit BACE1 to treat AD patients. This review summarizes the recent studies on the role of BACE1 in synaptic functions as well as our views on BACE1 inhibition as an effective AD treatment.
阿尔茨海默病（AD）是最常见的与年龄相关的痴呆症病因，也是全球范围内最重大的医疗保健问题之一。更糟糕的是，目前经美国食品和药物管理局（FDA）批准用于 AD 治疗的药物并不能预防或延缓疾病进展。因此，为 AD 患者开发有效的治疗方法迫在眉睫。过去三十年来，人类遗传和临床研究表明，淀粉样β（Aβ）肽的异常产生或积累可能是 AD 发病机制的罪魁祸首。Aβ 由淀粉样前体蛋白（APP）通过 β-位点 APP 切割酶 1（BACE1）（膜相关蛋白酶 2，β-分泌酶，Asp2 蛋白酶）和 γ-分泌酶的蛋白水解切割产生。BACE1 基因敲除的小鼠中 Aβ 的产生被阻断。因此，BACE1 的药理学抑制作为治疗 AD 患者的一种治疗方法正在被深入研究。BACE1 抑制剂临床试验的最近挫折突显了深入了解如何正确抑制 BACE1 以治疗 AD 患者的重要性。本综述总结了 BACE1 在突触功能中的作用的最新研究，以及我们对 BACE1 抑制作为有效 AD 治疗方法的看法。
