脑靶向抑制DMT1功能阻抑阿尔茨海默病转基因小鼠脑内β淀粉样蛋白沉积和tau蛋白异常磷酸化的分子机制

项目名称： 脑靶向抑制DMT1功能阻抑阿尔茨海默病转基因小鼠脑内β淀粉样蛋白沉积和tau蛋白异常磷酸化的分子机制

项目编号： No.81471112

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： 郑玮

作者单位： 中国医科大学

项目金额： 70万元

中文摘要： DMT1分布和表达异常是阿尔茨海默病(AD)脑内金属离子稳态失衡的原因之一，也是引起Aβ产生和沉积并造成神经元损伤的关键因素，因此DMT1已经成为AD治疗的重要靶点。在前期工作中，我们发现干扰DMT1功能不但能减少Aβ生成和tau蛋白异常磷酸化，还能拮抗可溶性Aβ寡聚体对神经元和突触的损伤。本项目以PS1/APP/tau三转基因小鼠为研究对象，DMT1小分子抑制物Ferristatin和Ebselen凝胶制剂经鼻黏膜吸收和脑靶向壳寡糖纳米粒经尾静脉注射给药，并构建中枢神经系统slc11a2基因Knock-down的PS1/APP双转基因小鼠。对小鼠脑内Aβ老年斑形成、NFTs缠结和神经元凋亡等相关指标进行检测，结合体外实验，不仅进一步揭示DMT1参与AD发病的机制，还可以为明确DMT1能否作为AD治疗靶点以及选择有效给药途径和治疗策略提供理论依据和技术支持。

中文关键词： 阿尔茨海默病；β淀粉样蛋白；tau蛋白；DMT1；APP/PS1/tau转基因小鼠

英文摘要： One of the reasons accounting for metal dyshomeostasis in AD brains is the abnormal distribution and expression of the divalent metal transporter, DMT1, which is also the key factor that causes abeta production and accumulation and neuronal injury. Therefore, DMTI has become the therapeutic target for AD. In our previous work, we have found that inhibiting the metal-transport function of DMTI can reduce the expression of abeta and abnormal phosphorylation of tau as well as prevent the neuronal and synaptic injury caused by abeta oligomers. All these studies would become the foundation of AD therapy theoretically and technically. The study subject of this project is PS1/APP/tau transgenic mice. We would administrate the Ferristatin and Ebselen gel through nasal mucosa or through caudal injection carrying brain-target chitosan nanoparticles. And we also tend to knock out gene slc11a2 in PS1/APP mice using neuron-specific promoters. Then detect a series of indicators, including abeta senile, NTFs and neuronal apoptosis. With the in vitro experiments, not only can the research reveal the involvement of DMTI in AD pathogenesis, it also can contribute a lot to the identification of DMT1 as a therapeutic target of AD and to the evidence supporting how to choose a practical and effective way for AD treatment.

英文关键词： Alzheimer's Disease;beta-amyloid;tau;DMT1;APP/PS1/tau transgenic mouse