抗Aβ31-35单克隆抗体在阿尔茨海默病APP/PS1转基因鼠中的实验研究

项目名称： 抗Aβ31-35单克隆抗体在阿尔茨海默病APP/PS1转基因鼠中的实验研究

项目编号： No.31271201

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 祁金顺

作者单位： 山西医科大学

项目金额： 80万元

中文摘要： 阿尔茨海默病（AD）认知功能下降与患者脑内淀粉样β蛋白（Aβ）的聚集和毒性密切相关。近年来以清除Aβ为目的的免疫疗法令人瞩目，但临床试验却因严重副作用而暂停，这与细胞膜上生理性淀粉样前体蛋白（APP）受到错误攻击有关。因此，设计和使用既能有效清除Aβ又不伤害APP的特异性抗体有望突破AD治疗瓶颈。本课题在以往确认Aβ活性中心的基础上，将巧妙利用31-35序列在APP结构域上的分布特征，采用基因工程噬菌体展示肽库技术制备选择性结合Aβ而规避APP的抗Aβ31-35单克隆抗体；将利用APP/PS1转基因鼠，研究抗Aβ31-35单克隆抗体预防和逆转AD动物病理性脑损伤及认知功能下降的神经保护效应；并通过检测AD转基因鼠在体海马场电位、脑片离子通道电流、培养细胞钙水平和脑内炎性反应因子等，阐明抗Aβ31-35单克隆抗体神经保护效应的细胞和分子机制。从而为AD防治提供一种安全、有效和新颖的免疫策略。

中文关键词： 抗Aβ31-35单链抗体；APP/PS1转基因鼠；淀粉样β蛋白；淀粉样前体蛋 白；阿尔茨海默病

英文摘要： The cognitive impairments in Alzheimer disease (AD) are closely related to the deposition and neurotoxicity of amyloid β protein (Aβ) in the brain. Although the immunotherapy aimed at clearing Aβ obtained remarkable achievements in recent years, the clinical trials of AD immunotherapy have been suspended because of serious side effects of anti-Aβ antibody, in which the physiological amyloid precursor protein (APP) was mistakenly attacked by anti-Aβ antibody. Therefore, it is very critical to prepare a specific antibody against Aβ but without any hurt to APP. Based on our previous finding that the sequence 31-35 of Aβ is the active center of Aβ molecule, the present study will prepare a specific monoclonal antibody against sequence 31-35 of Aβ by using phage display peptide library technology. On this basis, we will investigate the neuroprotective effects of anti-Aβ31-35 monoclonal antibody against the cerebral pathological impairments and cognitive deficits seen in APP/PS1 transgenic mouse. Further, the cellular and molecular mechanisms of anti-Aβ31-35 monoclonal antibody will be examined by recording in vivo hippocampal field potential, brain slice ion channel currents, intracellular calcium level and cerebral inflammatory factors in the brain. Overal, the study will try to provide a novel, safer and more effec

英文关键词： Anti-Aβ31-35 single chain antibody；APP/PS1 transgenic mouse；amyloid β protein；amyloid procursor protein；Alzheimer's disease