Aβ and human amylin share a common toxicity pathway via mitochondrial dysfunction
Aβ and human amylin share a common toxicity pathway via mitochondrial dysfunction
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DOI：
10.1002/pmic.200900651
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发表时间：
2010-04-01
期刊：
影响因子：
3.4
通讯作者：
Goetz, Juergen
中科院分区：
文献类型：
--
作者：
Lim, Yun-An;Rhein, Virginie;Goetz, Juergen
阿尔茨海默病（AD）和2型糖尿病（T2DM）是老年人发病和死亡的主要原因。这两种疾病的特征在于靶组织中的淀粉样蛋白沉积：T2DM中胰淀素的聚集与胰岛素分泌β细胞的损失相关，而AD脑中的淀粉样蛋白β（A β）聚集与神经元损失相关。在这里，我们使用定量iTRAQ蛋白质组学作为发现工具，以显示All和人胰淀素（HA）对相同的蛋白质（其中四分之一是线粒体）进行去调节，支持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，在用HA或A β处理后，线粒体复合物IV活性显著降低，线粒体呼吸也是如此。相比之下，复合物I活性仅在用HA处理后降低。A β和HA，但不是非淀粉样蛋白生成大鼠胰淀素，诱导ROS的产生显着增加。HA和A β的共孵育没有产生ROS产生的增强效应，再次表明共同的毒性机制。总之，我们的数据表明，A[3]和HA都发挥毒性，至少部分地，通过线粒体功能障碍，因此恢复其功能可能是有益的AD和T2DM。
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 All and human amylin (HA) deregulate identical proteins, a quarter of which are mitochondria], 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 mitochondria] 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[3 and HA both exert toxicity, at least in part, via mitochondrial dysfunction, thus restoring their function may be beneficial for both AD and T2DM.