Characterization of BACE-mediated proteolysis including amyloid-beta

老年斑是阿尔茨海默病（AD）的病理标志，其主要成分是淀粉样蛋白β42 （a - β42）。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释放β淀粉样蛋白前体（βAPP）以产生CTF-13，至少截断两个位点的Aβ。有趣的是，截断的Aβ比全长的Aβ聚集速度慢得多，因此BACE截断Aβ可能会促进Aβ的降解。重要的是，BACE还截断了高度聚集的致病性a - β42。在对BACE1进行诱变的基础上，我们尝试获得截断Aβ bun且不脱落βAPP的BACE突变体。我们最终发现，跨膜结构域缺失的BACE1保持了Aβ降解活性，而不脱落bAPP。因此，引入这种酶可用于增强致病性Aβ物种

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