中文摘要：

【目的】探讨线粒体未折叠蛋白反应（UPR^mt）对阿尔茨海默病（AD）Aβ蛋白聚集毒性的影响。【方法】将秀丽线虫（Caenorhabditis elegans）线粒体外膜tomm-22、内膜E04A4．5以及Ⅱ帕-1基因克隆并构建L4440干扰载体，转化HT115感受态细胞以制备tomm-22、E04A4．5和atfs-1 RNA干扰菌。研究tomm-22和E04A4.5RNA干扰对转基因线虫AD疾病模型CL4176和CL2006瘫痪进程的影响。观察torero-22和E04A4．5RNA干扰后野生型线虫N2寿命，检测ATFS-1信号在抑制AB蛋白聚集毒性中的作用，分析tomm-22和E04A4．5RNA干扰后转基因线虫SJ4100UPR^mt动态变化，以及转基因线虫DA2123自噬水平。【结果】通过对线虫线粒体tomm-22和E04A4．5基因克隆及构建RNA干扰菌建立了UPR^mt模型，证实能够抑制AD疾病模型CL4176a13蛋白聚集毒性并延缓其瘫痪进程。野生型N2在喂食tomm-22和E04A4．5RNA干扰菌后寿命明显缩短，而渐进性瘫痪线虫AD模型CL2006呈现前期延缓瘫痪而后期加速瘫痪的生理现象，说明UPR“呈现短期缓解线粒体应激和改善线粒体功能的调节作用。通过atfs-1 RNA干扰证实延缓线虫AD模型CL4176瘫痪进程与ATFS-1信号不直接相关。然而，tomm-22和E04A4．5RNA干扰后UPR^mt呈现逐渐增强的趋势，并进一步诱导自噬相关分子LGG-1的上调表达，提示RNA干扰延缓AD瘫痪进程是通过提高线虫体内自噬活性而发挥作用。【结论】线粒体UPR^mt通过协调线粒体与细胞核之间的信号转导能够抑制A13蛋白聚集毒性，有助于恢复线粒体乃至细胞内蛋白质稳态，保障细胞正常生理功能，为AD等神经退行性疾病的早期预防和治疗提供新的靶点。

英文摘要：

[Objective] To investigate the effects of mitochondrial unfolded-protein response （UPR^mt） on the aggregation toxicity of Aβ protein in Alzheimer＇s disease （AD）. [Methods] By cloning the mitochondrial outer membrane torero-22, inner membrane EO4A4.5 and atfs-1 genes of Caenorhabditis elegans （C. elegans ） and constructing the L4440 interference vectors, HT115 competent cells were transformed to prepare tomm-22, EO4A4.5 and atfs-1 RNAi bacteria. The effects of torero-22 and EO4A4.5 RNAi on the process of paralysis were investigated through transgenic AD disease models CL4176 and CL2006. The life span of wild type N2 C. elegans was observed after RNAi of tomm-22 and EO4A4.5. The regulatory role of ATFS-1 signaling by atfs-1 RNAi in inhibition of Aβ protein aggregation was detected. The dynamic changes of UPRm＇ in transgenic SJ4100 nematode and the autophagy level in transgenie DA2123 nematodes were analyzed by torero-22 and E04A4.5 RNAi. [ Results ] We successfully established the UPRa＇ model by cloning mitoehondrial torero-22 and E04A4.5 of C. elegans and further constructing RNAi bacteria, and showed that they can suppress aggregation toxicity of Amyloid-β （Aβ） protein in AD model CL4176. and slow down paralysis process. The life span of wild type N2 was significantly shortened after feeding with the tomm-22 and EO4A4.5 RNAi bacteria. At the same time, the progres- sive paralysis AD model CL2006 shows a delayed paralysis in the early stage of life cycle but get acceleration in the late. These re- sults illustrate that the UPR^mt can alleviate the mitochondrial stress and improve the function of mitochondria at least in the short term. The atfs-1 RNAi confirmed that delayed paralysis process of AD model CL4176 is not directly related to the ATFS-1 signal. Howev- er, tomm-22 and EO4A4.5 RNAi can gradually increase the UPR^mt response and induce the expression level of autophagy-related molecules LGG-1, suggesting that tomm-22 and EO4A4.5 RNAi may play a role in delaying the AD disease proc