Aβ3-10重复片段质粒免疫对APPswe/PSEN1双转基因鼠β淀粉样蛋白产生通路的影响及其机制的研究

项目名称： Aβ3-10重复片段质粒免疫对APPswe/PSEN1双转基因鼠β淀粉样蛋白产生通路的影响及其机制的研究

项目编号： No.81200834

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 马英

作者单位： 中国医科大学

项目金额： 23万元

中文摘要： Aβ疫苗研究以往只关注其对Aβ沉积清除及机制，忽略了对Aβ沉积产生通路的影响。APP通过α和β两个途径代谢，BACE1及γ分泌酶是控制β途径Aβ形成重要的蛋白酶。我们的研究Aβ3-10重复片段质粒改善APPswe/PSEN1双转基因鼠记忆和认知功能的损害是通过降低Aβ沉积和炎症反应，那么质粒对Aβ沉积和炎症反应的下调是否会影响Aβ产生通路呢？是否会影响BACE1/APP/γ分泌酶的表达及活性呢？机制是什么？所以拟应用Aβ3-10重复片段质粒免疫3、12月龄的APPswe/PSEN1双转基因鼠，设置空白及正常C57BL/6J对照组，检测质粒免疫中转基因鼠脑内Aβ沉积形成前及之后BACE1/APP/γ分泌酶蛋白及mRNA水平、BACE1分布及其与Aβ沉积的关系、神经元及被激活星形胶质细胞中BACE1表达水平、NF-κB水平的变化。探讨Aβ3-10重复片段质粒免疫对Aβ沉积产生通路影响及机制。

中文关键词： 阿尔茨海默病；β-淀粉样蛋白；核因子-κB；β分泌酶；γ分泌酶

英文摘要： In the past, only the clearance of Aβ deposition and its mechanisms were concerned during Aβ vaccine researches, and Aβ deposition formation pathway was ignored. There are two ways of APP metabolism: α and β pathway. BACE1 and γ-secretase are important proteases to control Aβ formation during β pathway. Our study has demonstrated Aβ3-10 repeat fragment plasmid improve memory and cognitive function impairment of Tg-APPswe/PSEN1dE9 mice by reducing Aβ deposition and inflammatory response. But whether the reduction of Aβ deposition and inflammatory response by the plasmid will affect Aβ generation pathway? Whether it will affect the expression and activity of BACE1/APP/γ-secretase? What is the mechanism? Therefore, Aβ3-10 repeat fragment plasmid will be applied to immune 3,12-month-old Tg-APPswe/PSEN1dE9 mice, and blank and normal C57BL/6J control groups will be set. The changes of BACE1/APP/γ-secretase protein and mRNA level, BACE1 distribution and its relationship with Aβ deposition, BACE1 expression in neuron and activated astrocyte, and NF-κB level will be detected during plasmid immunity before and after Aβ deposition formation in the brain of transgenic mice. Explore the effect and mechanism of Aβ deposition formation pathway during Aβ3-10 repeat fragment plasmid immunity.

英文关键词： Alzheimer disease；Aβ；NF-κB；BACE1；γ-secratase