Northwestern University, Feinberg School of Medicine, Department of Cell and Molecular Biology, Chicago, Illinois, USA.
J Neurochem. 2012 Jan;120 Suppl 1:55-61. doi: 10.1111/j.1471-4159.2011.07512.x. Epub 2011 Nov 28.
Our knowledge of the etiology of Alzheimer's disease (AD) has advanced tremendously since the discovery of amyloid beta (Aβ) aggregation in diseased brains. Accumulating evidence suggests that Aβ plays a causative role in AD. The β-secretase enzyme, beta-site APP cleaving enzyme-1 (BACE1), is also implicated in AD pathogenesis, given that BACE1 cleavage of amyloid precursor protein is the initiating step in the formation of Aβ. As a result, BACE1 inhibition has been branded as a potential AD therapy. In this study, we review the identification and basic characteristics of BACE1, as well as the progress in our understanding of BACE1 cell biology, substrates, and phenotypes of BACE1 knockout mice that are informative about the physiological functions of BACE1 beyond amyloid precursor protein cleavage. These data are crucial for predicting potential mechanism-based toxicity that would arise from inhibiting BACE1 for the treatment or prevention of AD.
自发现病变大脑中淀粉样 β（Aβ）聚集以来，我们对阿尔茨海默病（AD）病因的认识有了极大的提高。越来越多的证据表明 Aβ 在 AD 中起致病作用。β-分泌酶，β-位点 APP 裂解酶-1（BACE1）也与 AD 发病机制有关，因为 BACE1 对淀粉样前体蛋白的切割是 Aβ 形成的起始步骤。因此，BACE1 抑制已被认为是一种潜在的 AD 治疗方法。在这项研究中，我们回顾了 BACE1 的鉴定和基本特征，以及我们对 BACE1 细胞生物学、底物的理解的进展，以及 BACE1 敲除小鼠的表型，这些信息对于了解 BACE1 在淀粉样前体蛋白切割之外的生理功能非常重要。这些数据对于预测因抑制 BACE1 治疗或预防 AD 而产生的潜在基于机制的毒性至关重要。
