莲房原花青素调控ERS-UPR信号传导通路对阿尔茨海默氏病的防治作用及机制研究

项目名称： 莲房原花青素调控ERS-UPR信号传导通路对阿尔茨海默氏病的防治作用及机制研究

项目编号： No.81472978

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘烈刚

作者单位： 华中科技大学

项目金额： 85万元

中文摘要： 阿尔茨海默氏病（AD）是进行性认知功能障碍和记忆损害的脑退行性疾病，缺乏有效的防治药物。新近研究表明，内质网应激（ERS）和未折叠蛋白反应（UPR）参与AD的发生并贯穿始终，尤其在其两个特征性病变（老年斑和神经元纤维缠结）早期阶段发挥重要的神经保护作用。莲房原花青素（LSPC）是迄今为止活性最强的原花青素产品，能显著改善老年记忆/认知障碍，但具体机制不明，研究表明原花青素单体和低聚体能通过调节ERS-UPR保护神经细胞，据此推测LSPC可能通过调节ERS和增强UPR，抑制或阻止早期AD特征性病变的形成而发挥作用。本项目拟以转基因Tg2576小鼠为AD模型，以ERS-UPR通路与AD特征性病变（老年斑和神经元纤维缠结）形成早期的相互作用为切入点，采用体内外试验相结合的方法，探讨ERS-UPR通路在LSPC改善AD认知障碍中的作用及机制，为探讨AD的发病机制并发现可能的新治疗方式奠定基础。

中文关键词： 莲房原花青素；阿尔茨海默病；内质网应激；未折叠蛋白反应；记忆/认知障碍

英文摘要： Alzheimer's disease (AD) is a relentlessly progressive neurodegenerative disorder and the most common cause of dementia in adults. The classic histopathological features consist of extracellular plaques of the amyloid-β peptide (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated aggregates of microtubule-associated protein tau. Despite decades of study, the molecular pathology of the disease remains unclear and the current treatment is little effective. Recent studies have shown that endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are closely in relevant to the onset and progression of AD, especially in the early stages of the two characteristic lesions. On the other hand, procyanidins extracted from the lotus seedpod (LSPC) have been proven to play a neuroprotective role in learning and cognitive impairment related to AD. Thus, we hypothesized that LSPC may inhibite or prevent the formation of characteristic lesions of AD through regulating ERS and enhancing UPR at an early stage, which could finally improves the process of cognitive decline and neurodegeneration. To explore the role and mechanism of ERS-UPR pathway in the ameliorative effects of LSPC on cognitive impairment of AD, the current project will use Tg2576 mice as a transgenic animal model of AD, and focus on the interaction between ERS-UPR pathway and the early formation of extracellular plaques and intracellular neurofibrillary tangles. Techniques such as gene transfection, and RNA interference, will be employed both in vivo and in vitro. The implementation of the project, may not only provide new clues for exploring the pathogenesis of AD, but also lay a foundation for the prevention and treatment.

英文关键词： Procyanidins extracted from the lotus seedpod;Alzheimer's disease;endoplasmic reticulum stress;unfolded protein response;memory/cognitive impairment