项目名称: 亲环蛋白D介导早期阿尔茨海默病突触线粒体功能障碍机制的研究
项目编号: No.81200847
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: 杜蘅
作者单位: 山东大学
项目金额: 24万元
中文摘要: 阿尔茨海默病(AD)是一种常见的老年神经系统变性病。线粒体功能障碍是AD的重要病变,与AD神经元损伤密切相关。突触部位线粒体是神经元中关键线粒体亚群,在AD中其损伤发生早于其他线粒体亚群。目前AD早期突触线粒体损伤的分子机制尚未阐明。资料表明线粒体亲环蛋白D(cypD)是引起线粒体膜通透性转换孔(mPTP)形成的重要因子。我们在前期实验基础上首次提出cypD在AD早期及其发展阶段参与AD突触线粒体损伤。我们将应用cypD基因改造动物,通过降低或提高cypD表达量从体内体外两方面探索在不同浓度内源性AD致病因子beta-淀粉蛋白(Aβ)作用下,cypD介导突触线粒体上mPTP形成,引起突触线粒体功能损伤及前突触部位突触线粒体转运分布障碍中的作用。同时观察阻断cypD对Aβ导致的突触线粒体损伤的保护机制。本研究首次阐明cypD参与AD尤其是AD早期突触线粒体损伤的机制,为AD防治提供新的思路。
中文关键词: 阿尔茨海默病;亲环蛋白D;线粒体膜通透性转换孔;ATP合成酶;寡霉素敏感相关蛋白
英文摘要: Alzheimer's disease (AD) is a severe neurodegenerative disease attacking aged people. Mitochondrial dysfunction is a hallmark pathology in AD and closely related to neurodegeneration in AD.Synaptic mitochondria are a critical subgroup of neuronal mitochondria. Synaptic mitochondrial dysfunction is an early pathological change in AD and occurs before injury in other subgroups of mitochondtia. The detail mechanisms of synaptic mitochondrial dysfunction in AD have not yet been elucidated. Previous studies have demonstrated that cyclophilin D is the initiator of mitochondrial permeability transition pore (mPTP) formation. Our previous study suggested the potential involvement of cypD in synaptic mitochondrial pathology in AD.In this study, we will focus on the role of cyclophilin D (cypD) in mediating synaptic mitochondrial dysfunction in AD at its early and progressing stages. We will employ cypD gene manipulat mice to perform the study. By decreasing or increasing the expression level of cypD, we will conduct in-depth in vivo and in vitro study into the impact of cypD in inducing mPTP fromation in synaptic mitochondria thusly resulting in synaptic mitochondrial functional deficits and damaged distribution at presynapses in an environment with various levels of endongenous Amyloid beta. We will also detrmine the ef
英文关键词: Alzheimer's disease;cyclophilin D;mitochondrial permeability transition pore;ATP synthase;oligomycin sensitivity conferring protein