【作者】 刘文；

【导师】 汪维云； 刘瑞田；

【作者基本信息】 安徽农业大学 ， 生物化学与分子生物学， 2016， 硕士

【摘要】 阿尔茨海默病(Alzheimer’s disease,AD)是最普遍的神经退行性疾病之一,占老年痴呆症病例的80%,主要症状表现为渐进性记忆损失、认知功能障碍以及语言障碍等。AD疾病像许多其他老年疾病一样,是由多重因素共同作用的结果。在病人脑内可以检测到多种分子损伤。AD病人脑实质中可观察到的主要病理特征为Aβ纤维在脑内细胞外沉积形成的老年斑(senile plaques,SP)和异常过度磷酸化的微管相关蛋白(tau蛋白)在细胞内聚集形成神经纤维缠结(neurofibrillary tangles,NFT)。淀粉样蛋白级联假说认为,脑实质中Aβ的沉积能够诱发一系列的神经元损伤和炎症反应,是导致AD病人病情发展的关键原因。随着研究的深入,淀粉样蛋白级联假说也发生了适当的修改和调整,但仍是目前唯一能真正推进研究的假说,根据这一假说,选择Aβ3作为药物靶点,具有较好的治疗潜能。茯砖茶是黑茶的一种,长期饮用具有调节代谢、保健预防的作用。从茯砖茶中,我们分离提纯出一种命名为茶山奈苷B的黄酮氧苷类新型天然化合物(YCF-2)。YCF-2的分子结构部分为山奈酚结构,在C-4’位置上有一个对香豆酸基团和一个含有山奈酚和对香豆酸的特性的新型吡喃鼠李糖基团。YCF-2能够通过直接抑制β分泌酶活性降低Aβ的产生。此外,YCF-2能够阻碍Aβ聚集产生纤维,加速成熟纤维的解聚,产生具有较低细胞毒性的异常寡聚体。这种异常寡聚体由于结构发生变化,不能作为催化"种子"促进Aβ单体聚集。YCF-2可以直接改善Aβ寡聚体对神经细胞毒性的影响,同时通过抑制小胶质细胞内NF-κB信号通路,减少神经元死亡、ROS的产生、炎症因子的释放和小胶质细胞的激活。这些结果证明,从茯砖茶中提取的YCF-2具有神经保护作用,降低炎症反应,具有应用于治疗AD的潜能。更多还原

【Abstract】 Alzheimer’s disease(AD),almost 80%in dementia,is one of the most common degenerative disease.The main neuropsychiatric symptoms in AD are gradual memory loss,cognitive dysfunction and language barrier.AD,like many other geriatric disorders,seems to be multifactorial in origin.Many molecular lesions have been detected in AD.Pathologic features are characterized by the extracellular senile plaques,constituted with mature amyloidal protein deposit,and intracellular neurofibrillary tangles(NFT),composed of hyper-phosphorylated abnormal tau.The amyloid cascade hypothesis holds that the deposition of the amyloid-β peptide induce a series of neuron damage and neuroinflammation in brain parenchyma and make a crucial step that ultimately leads to AD.With the further study,the amyloid cascade hypothesis has been made appropriate modification and adjustments,and it is still the only one serviceably progressing.Based on this hypothesis,choosing Aβ as the drug target will have a therapeutic proficiency for AD.Fuzhuan brick-tea(FBT)is classified in dark tea,can regulate metabolism,precaution and health protection with long-term drink.We isolated a novel multifunctional compound named camellikaempferoside B(YCF-2)from FBT.YCF-2 has a kaempferol as major structural part.At the C-4’position of YCF-2,there is one p-coumaric acid(p-CA)group and a novel structure of rhamnopyranosyl group with the properties of both kaempferol and p-CA.YCF-2 can directly reduce the production of Aβ by inhibit(3-secretase enzymatic activity.Moreover,YCF-2 can inhibit Aβ fibrillation,accelerate mature fibril disaggregation,and change normal oligomer formation by binding to Aβ42 oligomers.Abnormal Aβ oligomers induced by YCF-2 showed no neurotoxicity.The abnormal oligomers loss the abilities to function as the catalytic "Seed" to promote Aβ monomer aggregation.Furthermore,YCF-2 ameliorated Aβ-induced neuronal cell death,ROS production,inflammatory factor release,and microglia activation by blocking the NF-κB signaling pathway in microglia.Collectlively,YCF-2 isolating from FBT,protecting neuronal cells from Aβ-induced damage and reducing neuroinflammation,has a potential role in AD treatment.更多还原