以铁蛋白为载体的菊苣酸通过AMPK/GluT1信号分子抑制Tau蛋白过度磷酸化的作用及机制研究

抑制海马区神经细胞中的Tau蛋白过度磷酸化可有效预防阿尔兹海默病（AD）的发生。课题组前期研究发现多酚类化合物菊苣酸（CA）可在体外降低神经细胞中Tau蛋白磷酸化（p-Tau）的水平，但具体机制不清。本研究拟采用不同剂量CA干预P301S-Tau转基因小鼠，通过观察其学习记忆能力、海马区神经纤维缠结程度及p-Tau水平的变化，确定CA对小鼠脑部海马区神经细胞中Tau蛋白磷酸化的作用；构建三种细胞共培养的血脑屏障（BBB）模型，利用铁蛋白包埋技术提高CA通过BBB的效率，并利用质粒转染和siRNA干扰技术分别调节脑血管内皮细胞中AMPK/GluT1的表达，通过iTRAQ、蛋白免疫印迹等方法测定BBB中三种细胞的p-Tau水平，阐明CA通过调节AMPK/GluT1抑制Tau蛋白过度磷酸化的可能机制。本研究可为膳食中的活性成分高效通过BBB提供新方法，并为其用于预防AD的发生提供新思路。

Inhibition of Tau protein phosphorylation can prevent the occurrence of Alzheimer Disease (AD) effectively. Our previous researches have indicated that chicoric acid (CA) can inhibit the Tau protein phosphorylation, but the potential mechanisms remain unknown. In present study, we will use the P301S-Tau mice model and treat it with various doses of CA. After that, we will observe and compare the learning and memory ability, the levels of Tau protein phosphorylation and the neurofibrillary tangles in the brain to determine the effect of CA on Tau protein phosphorylation; and then we will construct the cell model of blood brain barrier (BBB) and improve the stability and the rate of CA transporting through the BBB by encapsulating CA inside ferritin. In addition, we will regulate the expressions of AMPK and GluT1 by plasmid transfection and siRNA intervention, and determine the p-Tau levels of cells constituting BBB to further elucidate the potential mechanism of CA to reduce Tau phosphorylation through regulating AMPK/GluT1. This study will provide new method for bioactive molecules in food transporting through BBB and will provide new ideas for AD prevention by using dietary bioactive components.