Devi Latha, Prabhu Badanavalu M, Galati Domenico F, Avadhani Narayan G, Anandatheerthavarada Hindupur K
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 2006 Aug 30;26(35):9057-68. doi: 10.1523/JNEUROSCI.1469-06.2006.
Mitochondrial dysfunction is one of the major intracellular lesions of Alzheimer's disease (AD). However, the causative factors involved in the mitochondrial dysfunction in human AD are not well understood. Here we report that nonglycosylated full-length and C-terminal truncated amyloid precursor protein (APP) accumulates exclusively in the protein import channels of mitochondria of human AD brains but not in age-matched controls. Furthermore, in AD brains, mitochondrially associated APP formed stable approximately 480 kDa complexes with the translocase of the outer mitochondrial membrane 40 (TOM40) import channel and a super complex of approximately 620 kDa with both mitochondrial TOM40 and the translocase of the inner mitochondrial membrane 23 (TIM23) import channel TIM23 in an "N(in mitochondria)-C(out cytoplasm)" orientation. Accumulation of APP across mitochondrial import channels, which varied with the severity of AD, inhibited the entry of nuclear-encoded cytochrome c oxidase subunits IV and Vb proteins, which was associated with decreased cytochrome c oxidase activity and increased levels of H2O2. Regional distribution of mitochondrial APP showed higher levels in AD-vulnerable brain regions, such as the frontal cortex, hippocampus, and amygdala. Mitochondrial accumulation of APP was also observed in the cholinergic, dopaminergic, GABAergic, and glutamatergic neuronal types in the category III AD brains. The levels of translocationally arrested mitochondrial APP directly correlated with mitochondrial dysfunction. Moreover, apolipoprotein genotype analysis revealed that AD subjects with the E3/E4 alleles had the highest content of mitochondrial APP. Collectively, these results suggest that abnormal accumulation of APP across mitochondrial import channels, causing mitochondrial dysfunction, is a hallmark of human AD pathology.
线粒体功能障碍是阿尔茨海默病（AD）主要的细胞内病变之一。然而，人类AD中线粒体功能障碍所涉及的致病因素尚未完全明确。在此我们报告，非糖基化的全长和C端截短的淀粉样前体蛋白（APP）仅在人类AD大脑线粒体的蛋白质导入通道中积累，而在年龄匹配的对照中则未出现。此外，在AD大脑中，与线粒体相关的APP与线粒体外膜转位酶40（TOM40）导入通道形成稳定的约480 kDa复合物，并与线粒体TOM40和线粒体内膜转位酶23（TIM23）导入通道TIM23形成约620 kDa的超复合物，呈“N（在线粒体内）-C（在细胞质外）”方向。APP在线粒体导入通道中的积累随AD严重程度而变化，抑制了核编码的细胞色素c氧化酶亚基IV和Vb蛋白的进入，这与细胞色素c氧化酶活性降低和H2O2水平升高有关。线粒体APP的区域分布在AD易损脑区，如额叶皮质、海马体和杏仁核中较高。在III类AD大脑的胆碱能、多巴胺能、GABA能和谷氨酸能神经元类型中也观察到了APP在线粒体中的积累。转位受阻的线粒体APP水平与线粒体功能障碍直接相关。此外，载脂蛋白基因型分析显示，具有E3/E4等位基因的AD受试者线粒体APP含量最高。总体而言，这些结果表明，APP在线粒体导入通道中的异常积累导致线粒体功能障碍，是人类AD病理学的一个标志。
