1State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
2Beijing Institute for Brain Disorders, 45 Changchun St, 100053 Beijing, China.
Commun Biol. 2019 Jan 8;2:13. doi: 10.1038/s42003-018-0253-x. eCollection 2019.
Alzheimer's disease (AD) and diabetes are clinically positively correlated. However, the connection between them is not clarified. Here, using as a model system, we show that reducing insulin signaling can effectively suppress the toxicity from Aβ (Amyloid beta 42) expression. On the other hand, Aβ 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 insulin-like peptides and Aβ 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 Aβ toxicity, our results suggest that insulin signaling is the main downstream executor of Aβ 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.
阿尔茨海默病（AD）和糖尿病在临床上呈正相关。然而，它们之间的联系尚不清楚。在这里，我们使用 作为模型系统，表明降低胰岛素信号可以有效抑制 Aβ（β淀粉样蛋白 42）表达的毒性。另一方面，Aβ 积累导致果蝇胰岛素样肽（ILPs）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胰岛素样肽和 Aβ 之间对胰岛素降解酶（IDE）活性的相互竞争。有趣的是，尽管大脑中的胰岛素信号活性增强，但外周胰岛素信号却降低了。虽然许多上游因素可能会改变 Aβ 的毒性，但我们的研究结果表明，胰岛素信号是 Aβ 损伤的主要下游执行者，因此可能成为非糖尿病患者治疗阿尔茨海默病的有希望的靶点。本研究解释了为什么糖尿病患者中发现更多的阿尔茨海默病病例。
