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

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.

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。

莲是中药中一种传统的中药材。莲房原花青素是从莲房中提取出的混合物，并具有抗氧化及调节血糖等作用。研究表明，LSPC能改善老年大鼠学习和记忆能力障碍。尚未有相关研究证明LSPC对AD的作用及影响。本研究通过细胞实验、代谢实验和动物实验，逐步证明了LSPC对于AD的作用和可能的机制。.细胞实验研究表明LSPC对于AD具有保护作用，其可改善AD细胞模型中的细胞形态改变及细胞凋亡现象。代谢实验表明，LSPC干预后多种成分在动物体内增加，且不同组织和血浆中的物质含量和形式各不相同。而LSPC干预后槲皮素在体内各个组织中的增加是由于LSPC中槲皮素葡萄糖酸苷所致。结合已有关于Q3G生物作用的研究报道，因此推测Q3G可能是LSPC对AD起保护作用的有效成分之一。动物实验进一步表明， Q3G可通过改善AD模型小鼠胰岛素抵抗，调节IRS-1丝氨酸化，从而提高小鼠的学习和记忆能力，因此Q3G可能是LSPC中改善阿尔兹海默疾病的有效成分。本研究为AD的预防与治疗提供新的思路和方案。