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首页> 外文期刊>Biochemistry >Identification of Presenilin 1-Selective γ-Secretase Inhibitors with Reconstituted γ-Secretase Complexes
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Identification of Presenilin 1-Selective γ-Secretase Inhibitors with Reconstituted γ-Secretase Complexes

机译：重构的γ-分泌酶复合物鉴定早老素1-选择性γ-分泌酶抑制剂

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Accumulation of the β-amyloid (Aβ) peptides is one of thenmajor pathologic hallmarks in the brains of Alzheimer’s disease (AD)npatients. Aβ is generated by sequential proteolytic cleavage of the amyloidnprecursor protein (APP) catalyzed by β-and γ-secretases. Inhibition of Aβnproduction by γ-secretase inhibitors (GSIs) is thus being pursued as antarget for treatment of AD. In addition to processing APP, γ-secretase alsoncatalyzes proteolytic cleavage of other transmembrane substrates, with thenbest characterized one being the cell surface receptorNotch.GSIs reduce Aβnproduction in animals and humans but also cause significant side effectsnbecause of the inhibition ofNotch processing.The development ofGSIs thatnreduce Aβ production and have lessNotch-mediated side effect liability is therefore an important goal. γ-Secretase is a largemembranenprotein complex with four components, two of which have multiple isoforms: presenilin (PS1 or PS2), aph-1 (aph-1a or aph-1b),nnicastrin, and pen-2.Here we describe the reconstitution of four γ-secretase complexes in Sf9 cells containing PS1u0001aph-1a, PS1u0001aph-n1b, PS2u0001aph-1a, and PS2u0001aph-1b complexes. While PS1u0001aph-1a, PS1u0001aph-1b, and PS2u0001aph-1a complexes displayed robust γ-nsecretase activity, the reconstituted PS2u0001aph-1b complex was devoid of detectable γ-secretase activity. γ-Secretase complexesncontaining PS1 produced a higher proportion of the toxic species Aβ42 than γ-secretase complexes containing PS2. Using thenreconstitution system, we identified MRK-560 and SCH 1500022 as highly selective inhibitors of PS1 γ-secretase activity. Thesenfindings may provide important insights into developing a new generation of γ-secretase inhibitors with improved side effect profiles.
机译：β-淀粉样蛋白（Aβ）肽的积累是阿尔茨海默氏病（AD）病人大脑中的主要病理标志之一。 Aβ是由β和γ分泌酶催化的淀粉样蛋白前体蛋白（APP）的顺序蛋白水解切割产生的。因此，正在寻求通过γ-分泌酶抑制剂（GSI）抑制Aβn产生作为治疗AD的靶标。除了加工APP外，γ-分泌酶还催化其他跨膜底物的蛋白水解切割，其特征之一是细胞表面受体Notch.GSI减少了动物和人类的Aβn产生，但由于抑制Notch加工而引起了显着的副作用.GSI的发展因此，Aβ的产生和Notch介导的副作用的责任较少是一个重要的目标。 γ-分泌酶是一种大型的膜蛋白复合物，具有四个成分，其中两个具有多种同工型：早老素（PS1或PS2），aph-1（aph-1a或aph-1b），nastastrin和pen-2。包含PS1u0001aph-1a，PS1u0001aph-n1b，PS2u0001aph-1a和PS2u0001aph-1b复合物的Sf9细胞中的四种γ-分泌酶复合物。虽然PS1u0001aph-1a，PS1u0001aph-1b和PS2u0001aph-1a复合物显示出强健的γ-分泌酶活性，但重构的PS2u0001aph-1b复合物却没有可检测的γ-分泌酶活性。含有PS1的γ-分泌酶复合物比含有PS2的γ-分泌酶复合物产生更高比例的有毒物质Aβ42。使用然后重建系统，我们确定了MRK-560和SCH 1500022是PS1γ-分泌酶活性的高度选择性抑制剂。这些发现可能为开发具有改善的副作用效果的新一代γ-分泌酶抑制剂提供重要的见识。

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