γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP).
γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP).
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DOI：
10.1371/journal.pone.0144758
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Koo EH
中科院分区：
文献类型：
--
作者：
Lessard CB;Cottrell BA;Maruyama H;Suresh S;Golde TE;Koo EH
家族性阿尔茨海默病（FAD）相关APP和PSEN突变中Aβ42肽的相对增加可能与ε-裂解位点的利用和随后的分步切割的变化有关。ε-位点的断裂释放淀粉样蛋白前体蛋白（APP）胞内结构域（AICD），而ε-断裂位置的扰动与产生和分泌淀粉样蛋白β (Aβ)种类的变化密切相关。γ-分泌酶调节剂（GSMs）或FAD突变影响各种γ-分泌酶裂解从而改变Aβ肽生成的机制尚未完全阐明。最近的研究表明，gsm不调节APP的ε-裂解，但数据主要来自于重组截断表位标记的APP底物。在这里，我们利用转染细胞的全长APP，研究了GSMs是否在更自然的条件下修饰APP的ε-裂解。我们的结果证实了前人的发现，ε-裂解对gsm不敏感。此外，非诺贝特是一种逆GSM (iGSM)，在体外不改变ε-裂解位置或动力学。γ-分泌酶复合体的亚基APH1A和APH1B也能调节a - β42/ a - β40的比值，而ε-裂解没有任何改变，这与PS1和APP FAD突变的结果相反。因此，gsm和APH1似乎通过改变加工能力而不是ε-裂解位点利用来调节γ-分泌酶活性和a - β42的产生。
The relative increase in Aβ42 peptides from familial Alzheimer disease (FAD) linked APP and PSEN mutations can be related to changes in both ε-cleavage site utilization and subsequent step-wise cleavage. Cleavage at the ε-site releases the amyloid precursor protein (APP) intracellular domain (AICD), and perturbations in the position of ε-cleavage are closely associated with changes in the profile of amyloid β-protein (Aβ) species that are produced and secreted. The mechanisms by which γ-secretase modulators (GSMs) or FAD mutations affect the various γ-secretase cleavages to alter the generation of Aβ peptides have not been fully elucidated. Recent studies suggested that GSMs do not modulate ε-cleavage of APP, but the data were derived principally from recombinant truncated epitope tagged APP substrate. Here, using full length APP from transfected cells, we investigated whether GSMs modify the ε-cleavage of APP under more native conditions. Our results confirmed the previous findings that ε-cleavage is insensitive to GSMs. In addition, fenofibrate, an inverse GSM (iGSM), did not alter the position or kinetics of ε-cleavage position in vitro. APH1A and APH1B, a subunit of the γ-secretase complex, also modulated Aβ42/Aβ40 ratio without any alterations in ε-cleavage, a result in contrast to what has been observed with PS1 and APP FAD mutations. Consequently, GSMs and APH1 appear to modulate γ-secretase activity and Aβ42 generation by altering processivity but not ε-cleavage site utilization.