Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria.
Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria.
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DOI：
10.3233/jad-2011-101716
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Yan SS
中科院分区：
文献类型：
--
作者：
Alikhani N;Guo L;Yan S;Du H;Pinho CM;Chen JX;Glaser E;Yan SS
淀粉样蛋白β肽（Aβ）是一种与阿尔茨海默病（AD）发病机制有关的神经毒性肽，已在阿尔茨海默病患者和阿尔茨海默病转基因小鼠模型的脑线粒体中发现了积累。线粒体中Aβ的存在导致自由基的产生和神经元应激。最近，我们发现位于哺乳动物线粒体基质中的前序蛋白酶（PreP）是一种新的线粒体a β降解酶。在本研究中，我们检测了人脑颞叶线粒体基质中的PreP活性，颞叶是大脑中对Aβ积累和活性氧（ROS）产生高度敏感的区域。我们发现，与非AD年龄匹配的对照组相比，AD大脑中的hPreP活性显著降低。相比之下，在小脑中，一个通常不存在a β积累的大脑区域，当将AD样本与非AD对照组进行比较时，hPreP活性没有显着差异。我们还发现，与非转基因年龄匹配小鼠相比，AD转基因小鼠大脑线粒体基质（Tg mAβPP和Tg mAβPP/ABAD）中的PreP活性显著降低。此外，与非AD和非Tg小鼠相比，从AD大脑和Tg mAβPP小鼠中分离的线粒体组分具有更高水平的4-羟基壬烯醛（一种氧化产物）。因此，细胞色素c氧化酶活性在AD线粒体中显著降低。这些发现表明，PreP蛋白水解活性的降低，可能是由于ROS产生的增加，有助于线粒体中Aβ的积累，导致线粒体毒性和神经元死亡，这在AD中加剧。因此，PreP对线粒体Aβ的清除可能在AD的病理中起重要作用。
Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.