抗凋亡蛋白ARC调节beta-淀粉样蛋白线粒体毒性作用的机理研究

Increased life expectancy causing Alzheimer's disease (AD) become the fourth largest human killer today. It will have to spend 1% of global gross domestic product (GDP) on AD throughout the year. It is not only a medical problem, and it is fast becoming a major social problem. Synaptic dysfunction and loss of synapses are closely associated with cognitive impairment in AD patients. Mitochondria are essential for synapse formation, function and plasticity. Increasing evidence suggests that the accumulation of Aβ in synapses and synaptic mitochondria lead to synaptic mitochondrial failure and synaptic degeneration in AD. Our study have shown that ARC (Apoptosis Repressor with Caspase recruitment domain), an anti-apoptotic protein that is found abundantly in terminally differentiated cells, inhibited Aβ-induced toxicity by regulating mitochondrial fission and fusion. We intend to explore the molecular mechanisms of ARC in preventing Aβ-induced mitochondrial toxicity. The study includes: (1) ARC regulates Aβ-induced mitochondrial toxicity; (2) ARC prevents Aβ-induced mitochondrial toxicity by located in mitochondria; (3) ARC prevents Aβ-induced mitochondrial toxicity by regulating intracellular calcium homeostasis; (4) Verify the protective effect of ARC in animal models. The theoretical significance of the study is improving the molecular mechanisms in the pathogenesis of AD. At the same time, it maps a new direction for prevention and treatment of AD.

由于人口预期寿命的增加，阿尔茨海默氏病（AD）已经成为威胁人类健康的第四大杀手,并且全年造成的经济损失约为全球国内生产总值（GDP）的1%。它不再仅是一个医学问题，而已成为一个重大的社会问题。突触的丢失和突触损害与AD患者认知功能减退关系最为密切。线粒体对突触的形成和可塑性至关重要。现在研究揭示Aβ聚集于突触和突触线粒体，导致AD神经元中线粒体动力学异常和突触变性。我们的研究发现ARC作为一种终末分化细胞中表达的抗凋亡蛋白，可通过调节线粒体分裂/融合动态平衡抑制Aβ的毒性作用。此申请项目拟探究ARC调节Aβ线粒体毒性的分子机理。研究内容包括：（1）ARC对Aβ线粒体毒性作用的调节；（2）是否通过其定位于线粒体发挥作用；（3）是否是其调节胞浆钙稳态的结果；（4）选用动物模型，观察ARC对Aβ线粒体毒性作用的调节及机制。此项研究对于丰富和完善AD发病机制的分子和细胞生物学理论具有重要意义。

在阿尔茨海默氏病（Alzheimer’s disease, AD）的发病过程中, Aβ是一个重要角色。现在的研究揭示Aβ可聚集于突触和突触线粒体，导致AD神经元中线粒体动力学异常和突触变性。本实验以电镜为观测手段，观测了AD模型鼠与野生型小鼠大脑皮质与海马部位神经元突触与线粒体情况。通过免疫荧光染色观测一种终末分化细胞中表达的抗凋亡蛋白ARC在脑内的表达，并系统观测其在海马CA1、CA3、和齿状回的表达情况。Aβ可引起神经元内线粒体分裂及线粒体相关蛋白表达的变化。ARC可缓解Aβ诱导的线粒体分裂，但其具体作用机制有待进一步深入研究。