Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, Frankfurt/Main, Germany.
Antioxid Redox Signal. 2012 Jun 15;16(12):1421-33. doi: 10.1089/ars.2011.4173. Epub 2012 Feb 28.
Intracellular amyloid beta (Aβ) oligomers and extracellular Aβ plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Aβ production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase Aβ generation and thereby initiate a vicious cycle further impairing mitochondrial function.
Complex I and III dysfunction was induced in a cell model using the respiratory inhibitors rotenone and antimycin, resulting in mitochondrial dysfunction and enhanced ROS levels. Both treatments lead to elevated levels of Aβ. Presence of an antioxidant rescued mitochondrial function and reduced formation of Aβ, demonstrating that the observed effects depended on ROS. Conversely, cells overproducing Aβ showed impairment of mitochondrial function such as comprised mitochondrial respiration, strongly altered morphology, and reduced intracellular mobility of mitochondria. Again, the capability of these cells to generate Aβ was partly reduced by an antioxidant, indicating that Aβ formation was also ROS dependent. Moreover, mice with a genetic defect in complex I, or AD mice treated with a complex I inhibitor, showed enhanced Aβ levels in vivo.
We show for the first time that mitochondrion-derived ROS are sufficient to trigger Aβ production in vitro and in vivo.
Several lines of evidence show that mitochondrion-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Aβ itself leads to mitochondrial dysfunction and increased ROS levels. We propose that starting from mitochondrial dysfunction a vicious cycle is triggered that contributes to the pathogenesis of sporadic AD.
细胞内淀粉样β（Aβ）寡聚体和细胞外 Aβ 斑块是散发性阿尔茨海默病（AD）进展的关键因素。然而，触发 Aβ 产生的分子信号在很大程度上仍不清楚。我们想知道线粒体来源的活性氧（ROS）是否足以增加 Aβ 的产生，从而引发一个恶性循环，进一步损害线粒体功能。
使用呼吸抑制剂鱼藤酮和安密妥那在细胞模型中诱导复合物 I 和复合物 III 功能障碍，导致线粒体功能障碍和 ROS 水平升高。这两种处理都导致 Aβ 水平升高。抗氧化剂的存在挽救了线粒体功能并减少了 Aβ 的形成，表明观察到的效应取决于 ROS。相反，过度产生 Aβ 的细胞表现出线粒体功能障碍，如线粒体呼吸受损、形态强烈改变和线粒体在细胞内的流动性降低。同样，这些细胞生成 Aβ 的能力部分被抗氧化剂降低，表明 Aβ 的形成也依赖于 ROS。此外，复合物 I 基因缺陷的小鼠或用复合物 I 抑制剂治疗的 AD 小鼠在体内显示出 Aβ 水平升高。
我们首次表明，线粒体来源的 ROS 足以在体外和体内触发 Aβ 的产生。
有几条证据表明，线粒体来源的 ROS 导致淀粉样前体蛋白的淀粉样形成过程增强，而 Aβ 本身导致线粒体功能障碍和 ROS 水平升高。我们提出，从线粒体功能障碍开始，就会触发一个恶性循环，这有助于散发性 AD 的发病机制。
