双酚A引起大脑胰岛素抵抗致早期认知的损伤及机制

项目名称： 双酚A引起大脑胰岛素抵抗致早期认知的损伤及机制

项目编号： No.81473012

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 肖杭

作者单位： 南京医科大学

项目金额： 70万元

中文摘要： 阿尔茨海默病（AD）已成为继心血管、肿瘤后对人类健康的重大威胁，且近年来呈年轻化趋势，除与年龄、遗传因素相关外，环境化学物暴露亦是致病危险因素，但其机制仍不清楚。双酚A作为一种典型，具拟雌激素作用的内分泌干扰物，广泛存在于食品、饮料包装材料中，与人们日常生活极为密切。我们既往研究显示，BPA暴露可导致成年及子代小鼠外周胰岛素抵抗，近期预实验我们发现BPA亦可引起脑胰岛素抵抗，上调AD早期病理性标志蛋白APP，p-tau表达。基于胰岛素信号在学习记忆中的重要作用，我们认为BPA暴露可能通过破坏脑胰岛素信号导致早期认知障碍形成。因此该课题以海马区胰岛素信号为主线，通过Moriss水迷宫、脑片膜片钳、雌激素受体敲除、AD模型小鼠，db/db及STZ建立的胰岛素抵抗模型，系统探讨BPA暴露引起的脑胰岛素信号紊乱与早期认知障碍形成的关系及机制，进而提供依据支持和潜在的干预靶点，具有重要的预防意义。

中文关键词： 双酚A；认知损伤；大脑胰岛素抵抗；能量代谢

英文摘要： Alzheimer's disease has become the major threats after cancer and cardiovascular disease,and it gains much more attention,since many younger patients are suffering from it.The environmental chemical exposure mighe be the key risk factors but not limit to age and genetic factors.However,the mechanisms are still poorly understood.BPA is widely used as the base compound in the manufacture of polycarbonate plastics for daily equipments.Our previous study indicated that BPA exposure contributed to peripheral insulin resistance in adult mice and even offspring. Intriguingly, we also discovered that BPA exposure resulted in brain insulin resistence. Meanwhile, the early stage of AD hallmarks, APP and p-tau were significantly increased.Therefore,we hypothesised that BPA exposure disrupted the brain insulin signals and finalized recognition defects which was based on the important performation of insulin signals in the brain. Therefore, in the present work, the moriss water maze,brain slice patch clamp,ERs knock out, APP/PSEN,db/db and STZ-induced insulin resistance mouse models were applied to investigate the associations between the brain insulin resistance and the early cognitive defects. These studies,taken together, might provide the newly insights into the interventional strategies for BPA-mediated brain insulin resistance and the corresponding cognitive defects.

英文关键词： BPA;cognitive impairment;brain insulin resistance;glucose metabolism