Karolinska Institutet and Dainippon Sumitomo Pharma Alzheimer Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
FASEB J. 2011 Jan;25(1):78-88. doi: 10.1096/fj.10-157230. Epub 2010 Sep 10.
Intracellular amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondria were found to be the target both for amyloid precursor protein (APP) that accumulates in the mitochondrial import channels and for Aβ that interacts with several proteins inside mitochondria and leads to mitochondrial dysfunction. Here, we have studied the role of mitochondrial γ-secretase in processing different substrates. We found that a significant proportion of APP is associated with mitochondria in cultured cells and that γ-secretase cleaves the shedded C-terminal part of APP identified as C83 associated with the outer membrane of mitochondria (OMM). Moreover, we have established the topology of the C83 in the OMM and found the APP intracellular domain (AICD) to be located inside mitochondria. Our data show for the first time that APP is a substrate for the mitochondrial γ-secretase and that AICD is produced inside mitochondria. Thus, we provide a mechanistic view of the mitochondria-associated APP metabolism where AICD, P3 peptide and potentially Aβ are produced locally and may contribute to mitochondrial dysfunction in AD.
细胞内淀粉样β肽（Aβ）与阿尔茨海默病（AD）的发病机制有关。研究发现，线粒体既是淀粉样前体蛋白（APP）的靶标，APP 在 线粒体的输入通道中积累，也是 Aβ的靶标，Aβ与线粒体内部的几种蛋白质相互作用，导致线粒体功能障碍。在这里，我们研究了线粒体 γ-分泌酶对不同底物的作用。我们发现，在培养的细胞中，相当一部分 APP 与线粒体相关，γ-分泌酶切割 APP 的被称为 C83 的脱落 C 端部分，该部分与线粒体的外膜（OMM）相关。此外，我们还确定了 C83 在 OMM 中的拓扑结构，并发现 APP 细胞内结构域（AICD）位于线粒体内部。我们的数据首次表明，APP 是线粒体 γ-分泌酶的底物，并且 AICD 在 线粒体内部产生。因此，我们提供了一种与线粒体相关的 APP 代谢的机制观点，其中 AICD、P3 肽和潜在的 Aβ在局部产生，可能导致 AD 中的线粒体功能障碍。
