Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
J Alzheimers Dis. 2011;27(1):75-87. doi: 10.3233/JAD-2011-101716.
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.
淀粉样β肽（Aβ）的积累，这种与阿尔茨海默病（AD）发病机制有关的神经毒性肽，已在 AD 患者和 AD 转基因小鼠模型的大脑线粒体中得到证实。Aβ在线粒体中的存在导致自由基的产生和神经元应激。最近，我们鉴定出位于哺乳动物线粒体基质中的前导序列蛋白酶 PreP 是一种新的线粒体 Aβ降解酶。在本研究中，我们检测了人颞叶大脑线粒体基质中的 PreP 活性，颞叶是大脑中极易积累 Aβ和产生活性氧（ROS）的区域。我们发现 AD 大脑中的 hPreP 活性明显低于非 AD 年龄匹配对照。相比之下，在小脑，一个通常免受 Aβ积累影响的大脑区域，AD 样本与非 AD 对照相比，hPreP 活性没有显著差异。我们还发现 AD 转基因小鼠大脑（Tg mAβPP 和 Tg mAβPP/ABAD）的线粒体基质中 PreP 活性明显降低，与非转基因老年匹配小鼠相比。此外，与非 AD 和非 Tg 小鼠相比，来自 AD 大脑和 Tg mAβPP 小鼠的线粒体级分中 4-羟基壬烯醛（一种氧化产物）的水平更高。相应地，AD 线粒体中的细胞色素 c 氧化酶活性显著降低。这些发现表明，PreP 蛋白水解活性的降低，可能是由于 ROS 产生增加所致，导致线粒体中 Aβ的积累，从而加剧 AD 中的线粒体毒性和神经元死亡。因此，PreP 清除线粒体 Aβ可能在 AD 的病理学中具有重要意义。
