Insulin signaling in Drosophila melanogaster mediates Aβ toxicity
Insulin signaling in Drosophila melanogaster mediates Aβ toxicity
复制标题
果蝇中的胰岛素信号介导 Aβ 毒性
DOI：
10.1038/s42003-018-0253-x
复制
发表时间：
2019-01-08
影响因子：
5.9
通讯作者：
Zhou, Bing
中科院分区：
文献类型：
--
作者：
Huang, Yunpeng;Wan, Zhihui;Zhou, Bing
阿尔茨海默病（AD）和糖尿病在临床上正相关。然而，它们之间的联系并没有得到澄清。在这里，使用果蝇作为模型系统，我们表明，减少胰岛素信号可以有效地抑制A β（淀粉样蛋白β 42）表达的毒性。另一方面，A β积累导致果蝇胰岛素样肽（ILP）的升高和大脑中胰岛素信号的激活。从机制上讲，这些观察结果归因于果蝇胰岛素样肽和A β之间对胰岛素降解酶（IDE）活性的相互竞争。有趣的是，尽管胰岛素在大脑中的活性增强，但外周胰岛素信号却减少了。虽然许多上游因素可能会改变A β毒性，但我们的研究结果表明，胰岛素信号传导是A β损伤的主要下游执行者，因此可以作为非糖尿病患者治疗阿尔茨海默病的有希望的靶点。这项研究解释了为什么在糖尿病患者中发现更多的阿尔茨海默氏症病例。
Alzheimer's disease (AD) and diabetes are clinically positively correlated. However, the connection between them is not clarified. Here, using Drosophila as a model system, we show that reducing insulin signaling can effectively suppress the toxicity from A beta (Amyloid beta 42) expression. On the other hand, A beta accumulation led to the elevation of fly insulin-like peptides (ILPs) and activation of insulin signaling in the brain. Mechanistically, these observations are attributed to a reciprocal competition between Drosophila insulin-like peptides and A beta for the activity of insulin-degrading enzyme (IDE). Intriguingly, peripheral insulin signaling is decreased despite its heightened activity in the brain. While many upstream factors may modify A beta toxicity, our results suggest that insulin signaling is the main downstream executor of A beta damage, and thus may serve as a promising target for Alzheimer's treatment in non-diabetes patients. This study explains why more Alzheimer's cases are found in diabetes patients.