姜黄素基于对APP表达和加工调节的神经营养作用及分子机制研究

The problems on nutrition and health caused by aging are the urgent tasks to deal with. APP is a protein closely related to the development of Alzheimer's disease, a common neurodegenerative disease. This fact suggests that the process of brain aging may be associated with the changes in expression or metabolism of APP. Based on the neurophysiological function of APP, on one hand, this project will carry out to investigate the expression, trafficking and proteolytic processing of APP during aging process of organism. On the other hand, this project will explore whether curcumin can delay the aging of brain and the degenerative process of APP and illuminate the underlying mechanisms. Firstly, the experiments use normal aging mice and oxidative stress-induced rapidly aging mice treated with D-galactose as aging animal model. The gene expression and proteolytic processing of APP are investigated during the process of aging and oxidative stress, and the delaying effects of curcumin on the aging process of mice and the inhibitory effects of curcumin on APP expression and proteolytic processing will be studied. Second, based on the experiments of cellular and molecular biology, this project further investigates the effects of oxidative stress, which is closely related to the aging process, on the post-translational modification, the cell membrane localization, and the proteolytic processing of APP. Furthermore, whether GSK-3β mediates the effects of curcumin on APP post-translational modification of APP, the cell membrane localization, and the proteolytic processing is explored. This project will provide not only the experimental data and theoretical support for clarifying the neurotrophic effect of curcumin but also a strategic guidance for the application of neurotrophic foods.

衰老所带来的老年人群营养和健康问题是我们需迫切解决的问题，大脑衰老变化过程可能与APP的表达或代谢变化相关。本课题以APP的神经生理功能为中心，探讨肌体衰老过程中大脑APP的代谢变化行为，进一步探索姜黄素能否延缓APP的衰老退变，并探究其分子机制。以自然衰老的小鼠和D-半乳糖致氧化应激衰老小鼠为实验动物模型，研究衰老过程中，大脑中APP蛋白的表达及裂解代谢行为，探索姜黄素对衰老小鼠的神经营养作用及对大脑APP的表达及裂解代谢行为的影响。进一步在细胞及分子水平上阐明与衰老过程密切相关的氧化应激水平对APP蛋白翻译后修饰、在细胞内转运、细胞膜定位及裂解代谢行为的影响及姜黄素的抑制作用机理，揭示GSK-3β介导姜黄素对APP蛋白翻译后修饰、细胞膜定位及裂解代谢过程调节的分子机制。本课题将为食品的神经营养应用研究提供策略参考，为食源性生物活性物质姜黄素的神经营养作用的阐明提供实验数据和理论基础。

我国已经进入人口老龄化社会，衰老所带来的老年人群营养和健康问题是我们需迫切解决的问题。阿尔茨海默是与年龄密切相关的疾病，年龄越大得阿尔茨海默病的风险越高，我国65岁以上老年人老年痴呆患病率约为6%，其中阿尔茨海默病(Alzheimer's disease, AD)性痴呆是老年痴呆的主要类型。目前我国65岁以上老人阿尔茨海默病发病率约为4%～6%，随着老龄化进程的加剧，我国阿尔茨海默病的患病率也将成逐年递增的趋势。β淀粉样前体蛋白(APP蛋白)是与神经退行性变阿尔茨海默病病程发展密切相关的分子，本项目以APP的神经生理功能为中心，探讨机体衰老过程中大脑APP的代谢变化行为，并探索姜黄素能否延缓APP的衰老退变过程，并探究其分析机制。本项目主要开展了以下研究：以自然衰老的小鼠/氧化应激衰老小鼠、神经退行性病变阿尔茨海默病模型大鼠为实验动物模型，研究大脑衰老过程中，APP蛋白的表达及裂解代谢行为，探索姜黄素能否延缓机体的衰老过程，以及姜黄素对APP的表达及裂解代谢行为的影响；进一步在细胞及分子水平上研究氧化应激水平对APP蛋白表达和裂解代谢行为的影响，探讨GSK-3β是否介导了姜黄素对APP蛋白的衰老退变作用的影响。.本项目的研究发现，.(1) 姜黄素能够改善氧化应激衰老小鼠、神经退行性病变阿尔茨海默病模型大鼠为实验动物模型动物的学习记忆能力,表明姜黄素能够延缓大脑衰老进程。.(2) 在氧化应激衰老小鼠、神经退行性病变阿尔茨海默病模型大鼠为实验动物模型动物和细胞体系实验中，机体衰老过程中APP蛋白表达升高，氧化应激状态下APP蛋白表达升高，姜黄素能够抑制APP蛋白表达的上调作用。APP695蛋白Thr668磷酸化对APP蛋白的裂解代谢有很大的影响作用，衰老导致APP695 Thr668磷酸化升高，姜黄素能够抑制该位点的磷酸化，这可能也与姜黄素降低APP经β-裂解途径剪切有关。.(3) 在体外培养的细胞体系实验中表明，GSK-3β活性调控了APP蛋白表达和裂解代谢的影响作用，这也可能与姜黄素对APP蛋白表达和裂解代谢相关。 .本课题部分回答了机体衰老AD样变化过程中APP蛋白变化作用，这种变化潜在性地揭示APP的可能生理功能，本课题的研究结果和数据也为食品或者药品AD病变的神经营养预防和治疗提供策略参考，为食源性生物活性物质姜黄素的神经营养作用的阐明提供实验数据和理论基础。