对香豆酸/乳铁蛋白/谷胱甘肽纳米复合物预防缺氧性认知功能障碍的作用及机制

阿尔茨海默病（AD）是我国重要的公共卫生问题，缺氧是导致AD的一个重要危险因素。目前，尚缺乏针对缺氧性认知功能障碍的防治方法。对香豆酸（CA）和乳铁蛋白（Lf）皆可改善认知功能，我们发现CA可改善缺氧性脑损伤，CA和Lf均可抑制HIF-1α的表达，而HIF-1α-C/EBPβ-AEP轴可能是介导缺氧性认知障碍的重要通路。因CA的血脑屏障透过率较低，我们已采用CA、Lf和具有脑靶向功能的谷胱甘肽（GSH）制备出CA/Lf/GSH纳米复合物。我们假设：该纳米复合物可通过调控HIF-1α-C/EBPβ-AEP轴来预防缺氧性认知功能障碍。本项目拟探究该纳米复合物的结构、体外穿膜能力和体内代谢分布，用PC12细胞和APP/PS1小鼠缺氧模型探究CA和Lf是否可协同增效改善认知，并探究该复合物对HIF-1α-C/EBPβ-AEP轴的调控作用，以揭示其作用机制。本研究可为营养干预防治AD提供理论依据。

Alzheimer’s disease (AD) is a major health issue in China. Hypoxia is an important risk factor for AD. At present, there is still a lack of prevention and treatment methods for hypoxic cognitive impairment. Both p-coumaric acid (CA) and lactoferrin (Lf) can improve cognitive function. We found out that CA could effectively prevent the hypoxic cerebral pathological damage; both CA and Lf can inhibit the expression of HIF-1α. Besides, HIF-1α-C/EBPβ-AEP axis may be an important pathway that mediate hypoxic cognitive impairment. Since CA possessed low blood-brain barrier penetration rate, thus we have utilized CA, Lf and glutathione (GSH), which can target to the brain, to form CA/Lf/GSH nanocomposite. We hypothesize that CA/Lf/GSH nanocomposite can prevent hypoxic cognitive impairment through regulation of HIF-1α-C/EBPβ-AEP axis. In this project, we will characterize the CA/Lf/GSH nanocomposite, evaluate its ability to cross the blood-brain barrier in vitro, and study its biodistribution in vivo. Then, PC12 cell hypoxic model and APP/PS1 mice hypoxic model will be utilized to study whether CA and LF in the nanocomposite may play a synergistic effect to improve cognitive function, and whether the nanocomposite can regulation HIF-1α-C/EBPβ-AEP axis to reveal its effect mechanism. This study may provide theoretical basis for nutritional intervention to prevent and treatment of AD.