Characterization of BACE-mediated proteolysis including amyloid-beta

老年斑是阿尔茨海默病（Alzheimer's disease，AD）的病理标志，其主要成分是淀粉样蛋白β 42（amyloid-beta42，Aβ42）。抑制Aβ生成或增强Aβ降解是开发治疗AD方法的基本途径。我们发现，BACE，脱落β-淀粉样蛋白前体（βAPP），以产生CTF-13，截短Aβ至少两个位点。有趣的是，截短的Aβ聚集速度比全长Aβ慢得多，因此BACE截短Aβ可能促进Aβ降解。重要的是，BACE还截短了高度聚集性、致病性Aβ42。在BACE 1突变的基础上，我们尝试获得Aβ bun截短而βAPP不脱落的BACE突变体。结果发现，缺失了跨膜结构域的BACE 1仍具有降解Aβ的活性，而不释放bAPP。因此，引入这种酶可用于增强致病性Aβ种类

Senile plaque is a pathological hallmark of Alzheimer's disease (AD) and its major component is amyloid-beta 42(Aβ42). Inhibition of Aβ generation or enhancement of Aβ degradation is fundamental approach in developing methods to treat AD. We revealed that BACE, which sheds beta-amyloid protein precursor (βAPP) to generate CTF-13, truncates Aβ at least two sites. Interestingly, truncated Aβ aggregated much slower than full length Aβ, thus the truncation of Aβ by BACE may promote Aβ degradation. Importantly, BACE also truncated highly aggregatable, pathogenic Aβ42. Based on mutagenesis of BACE1, we tried to obtain BACE mutants which truncate Aβ bun do not shed βAPP. We finally found that BACE1 of which the transmembrane domain is deleted maintained Aβ degrading activity, while it did not shed bAPP. Therefore, introduction of such an enzyme may be used to enhance pathogenic Aβ species