Alzheimer's & Parkinson's Disease Laboratory, Brain & Mind Research Institute, University of Sydney, Camperdown, Australia.
Proteomics. 2010 Apr;10(8):1621-33. doi: 10.1002/pmic.200900651.
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are leading causes of morbidity and mortality in the elderly. Both diseases are characterized by amyloid deposition in target tissues: aggregation of amylin in T2DM is associated with loss of insulin-secreting beta-cells, while amyloid beta (A beta) aggregation in AD brain is associated with neuronal loss. Here, we used quantitative iTRAQ proteomics as a discovery tool to show that both A beta and human amylin (HA) deregulate identical proteins, a quarter of which are mitochondrial, supporting the notion that mitochondrial dysfunction is a common target in these two amyloidoses. A functional validation revealed that mitochondrial complex IV activity was significantly reduced after treatment with either HA or A beta, as was mitochondrial respiration. In comparison, complex I activity was reduced only after treatment with HA. A beta and HA, but not the non-amyloidogenic rat amylin, induced significant increases in the generation of ROS. Co-incubation of HA and A beta did not produce an augmented effect in ROS production, again suggesting common toxicity mechanisms. In conclusion, our data suggest that A beta and HA both exert toxicity, at least in part, via mitochondrial dysfunction, thus restoring their function may be beneficial for both AD and T2DM.
阿尔茨海默病（AD）和 2 型糖尿病（T2DM）是老年人发病率和死亡率的主要原因。这两种疾病的特征都是在靶组织中出现淀粉样沉积：T2DM 中胰淀素的聚集与胰岛素分泌β细胞的丧失有关，而 AD 脑中的淀粉样β（Aβ）聚集与神经元丧失有关。在这里，我们使用定量 iTRAQ 蛋白质组学作为发现工具，表明 Aβ和人胰淀素（HA）都能调节相同的蛋白质，其中四分之一是线粒体的，这支持了线粒体功能障碍是这两种淀粉样变性的共同靶点的观点。功能验证显示，用 HA 或 Aβ处理后，线粒体复合物 IV 的活性和线粒体呼吸均显著降低，而复合物 I 的活性仅在 HA 处理后降低。Aβ和 HA 但不是非淀粉样的大鼠胰淀素会诱导 ROS 生成显著增加。HA 和 Aβ的共孵育不会增加 ROS 生成的增强作用，这再次表明存在共同的毒性机制。总之，我们的数据表明，Aβ和 HA 都通过线粒体功能障碍发挥毒性作用，因此恢复其功能可能对 AD 和 T2DM 都有益。
