Lin Sun, Wei Li, Ping Yang, Xia Li, Xiao Shifu
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Research Center for Model Organisms, Shanghai, China.
Neurosci Lett. 2018 Jan 18;664:152-159. doi: 10.1016/j.neulet.2017.11.022. Epub 2017 Nov 10.
In our previous work, we demonstrated the protective effect of BMP6 on neuron against Aβ toxicity in vitro. In the present study, our aim was to determine the effects of BMP6 in Aβ toxicity in vivo. Firstly, we evaluated the levels and localization of endogenous BMP6 in APP/PS1 transgenic mice. Secondly, dose-response effects of exogenous BMP6 and BMP6 pathway antagonists were tested in transgenic CL2006C. elegans (expressing Aβ3-42) lifespan and locomotor activity. We have three findings: 1) BMP6 was upregulated in the hippocampus in APP/PS1 mice. 2) The endogenous BMP6 is mainly expressed in the cytoplasm of neuron and nuclear of microglia, not in astrocyte in APP/PS1 mice. 3) BMP6 supplementation did not benefit transgenic worms, even toxic at certain concentrations, and antagonizing BMP downstream pathways including Smad and LIMK1 could alleviate the toxicity caused by 0.1μg/ml BMP6. The results suggest there is elevated BMP6 pathway in Aβ toxicity, and normalization of BMPs may be an important target for therapeutic intervention of AD.
在我们之前的工作中，我们证明了骨形态发生蛋白6（BMP6）在体外对神经元抵抗淀粉样β蛋白（Aβ）毒性具有保护作用。在本研究中，我们的目的是确定BMP6在体内对Aβ毒性的影响。首先，我们评估了APP/PS1转基因小鼠体内内源性BMP6的水平和定位。其次，我们在转基因CL2006秀丽隐杆线虫（表达Aβ3-42）的寿命和运动活性方面测试了外源性BMP6和BMP6信号通路拮抗剂的剂量反应效应。我们有三个发现：1）在APP/PS1小鼠的海马体中BMP6表达上调。2）在APP/PS1小鼠中，内源性BMP6主要在神经元的细胞质和小胶质细胞的细胞核中表达，而不在星形胶质细胞中表达。3）补充BMP6对转基因线虫没有益处，甚至在某些浓度下具有毒性，而拮抗包括Smad和LIMK1在内的BMP下游信号通路可以减轻0.1μg/ml BMP6所引起的毒性。结果表明，在Aβ毒性中BMP6信号通路升高，而使骨形态发生蛋白（BMPs）正常化可能是阿尔茨海默病（AD）治疗干预的一个重要靶点。
