Identification of BACE2 as an avid ß-amyloid-degrading protease.
Identification of BACE2 as an avid ß-amyloid-degrading protease.
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DOI：
10.1186/1750-1326-7-46
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发表时间：
2012-09-17
影响因子：
15.1
通讯作者：
Leissring MA
中科院分区：
文献类型：
--
作者：
Abdul-Hay SO;Sahara T;McBride M;Kang D;Leissring MA
降解淀粉样β蛋白（Aβ）的蛋白酶已成为阿尔茨海默病（AD）病因学及潜在治疗中的关键因素，但不太可能所有此类蛋白酶都已被识别出来。为了发现新的Aβ降解蛋白酶（AβDPs），我们进行了无偏向的、基因组规模的功能性cDNA筛选，旨在识别能够降低细胞产生的净Aβ水平的蛋白酶，随后使用一系列下游检测方法对其Aβ降解活性进行了表征。
筛选中脱颖而出的首要命中对象是β位点淀粉样前体蛋白切割酶2（BACE2），鉴于其近亲BACE1在Aβ产生中已确立的作用，这是一个相当意外的发现。已知BACE2能够通过对APP的非淀粉样生成加工来降低Aβ水平。然而，在体外，BACE2也被发现是一种特别活跃的AβDP，其催化效率超过除胰岛素降解酶（IDE）之外的所有已知AβDP。还发现BACE1也能降解Aβ，尽管其效率比BACE2低约150倍。Aβ在三个肽键——苯丙氨酸19 - 苯丙氨酸20、苯丙氨酸20 - 丙氨酸21和亮氨酸34 - 甲硫氨酸35处被BACE2切割，其中后一个切割位点是最初的也是主要的位点。在培养细胞中过表达BACE2被发现比多种已确立的AβDP（包括脑啡肽酶（NEP）和内皮素转化酶 - 1（ECE1））更能大幅降低净Aβ水平，同时显示出与IDE相当的效果。
这项研究确定了BACE2作为一种强效AβDP的新功能作用。基于其高催化效率、在细胞内降解Aβ的能力以及其他特性，BACE2是治疗或预防AD特别有潜力的治疗候选对象。
Proteases that degrade the amyloid ß-protein (Aß) have emerged as key players in the etiology and potential treatment of Alzheimer’s disease (AD), but it is unlikely that all such proteases have been identified. To discover new Aß-degrading proteases (AßDPs), we conducted an unbiased, genome-scale, functional cDNA screen designed to identify proteases capable of lowering net Aß levels produced by cells, which were subsequently characterized for Aß-degrading activity using an array of downstream assays. The top hit emerging from the screen was ß-site amyloid precursor protein-cleaving enzyme 2 (BACE2), a rather unexpected finding given the well-established role of its close homolog, BACE1, in the production of Aß. BACE2 is known to be capable of lowering Aß levels via non-amyloidogenic processing of APP. However, in vitro, BACE2 was also found to be a particularly avid AßDP, with a catalytic efficiency exceeding all known AßDPs except insulin-degrading enzyme (IDE). BACE1 was also found to degrade Aß, albeit ~150-fold less efficiently than BACE2. Aß is cleaved by BACE2 at three peptide bonds—Phe19-Phe20, Phe20-Ala21, and Leu34-Met35—with the latter cleavage site being the initial and principal one. BACE2 overexpression in cultured cells was found to lower net Aß levels to a greater extent than multiple, well-established AßDPs, including neprilysin (NEP) and endothelin-converting enzyme-1 (ECE1), while showing comparable effectiveness to IDE. This study identifies a new functional role for BACE2 as a potent AßDP. Based on its high catalytic efficiency, its ability to degrade Aß intracellularly, and other characteristics, BACE2 represents a particulary strong therapeutic candidate for the treatment or prevention of AD.
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