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The role of astrocytes in apoE4 related neurodegeneration.

星形胶质细胞在 apoE4 相关神经变性中的作用。

基本信息

批准号：
190311819
负责人：
Dr. Johanna Maria Knöferle
金额：
--
依托单位：
Gladstone Institutes
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/190311819?language=en
关键词：
role astrocytes apoE4 related neurodegeneration.

项目摘要

Alzheimer‘s disease (AD) is a neurodegenerative disorder with increasing incidence in the postindustrial world. Genetic causes as well as different predisposing factors have been discussed in the recent literature, pointing towards a multifactorial disease origin. A major genetic risk factor of familial and sporadic AD is apolipoprotein (apo) E4, one of the 3 apoE isoforms in humans with 65-80% of AD subjects being ApoE4 carriers. The molecular mechanisms underlying this association are not well understood, and no current therapies are based on apoE4 predisposition. Weisgraber et al from the Gladstone Institutes, San Francisco, determined unique changes in the structure of the apoE4 isoform that were predicted to affect its function: one such is domain interaction that leads to a compact protein structure. The group developed a mouse model that is selectively specific for domain interaction, the Arg-61 apoE mouse (model system in the present proposal). Studies in this model revealed that domain interaction in these mice leads to enhanced endoplasmic reticulum stress levels and induces astrocyte dysfunction, which consecutively might lead to impaired neuronal repair and maintenance. Animals exhibit cognitive dysfunction and learning disabilities similar to symptoms seen in AD. Thus, the contribution of Arg-61 apoE to neurodegeneration with a special focus on the role of astrocytes function will be examined in this proposal. Specific study aims will be 1) the direct dependence of astrocyte metabolism on Arg-61 apoE expression levels, 2) the possible role of Arg-61 apoE astrocytes as intrinsic components in the development of the Arg-61 apoE phenotype (cell autonomous vs. non cell autonomous contribution) 3) the significance of Arg-61 apoE as a predisposing factor for neurodegeneration in the presence of CNS insults. Insights in the mechanisms of apoE4/ Arg-61 apoE holds the potential open new therapeutic approaches in the treatment of a majority of AD subjects.

阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，在后工业时代发病率越来越高。遗传原因以及不同的诱发因素已在最近的文献中讨论，指向一个多因素的疾病起源。家族性和散发性AD的一个主要遗传风险因素是载脂蛋白（apo）E4，它是人类3种apoE亚型之一，65-80%的AD受试者是ApoE 4携带者。这种关联的分子机制还不清楚，目前没有基于apoE 4易感性的治疗方法。来自旧金山弗朗西斯科的Weisgraber等人确定了apoE 4同种型结构的独特变化，这些变化被预测会影响其功能：其中一个是导致紧凑蛋白质结构的结构域相互作用。该小组开发了一种对结构域相互作用具有选择性特异性的小鼠模型，即Arg-61 apoE小鼠（本提案中的模型系统）。在该模型中的研究表明，这些小鼠中的结构域相互作用导致内质网应激水平增强并诱导星形胶质细胞功能障碍，这可能连续导致神经元修复和维护受损。动物表现出认知功能障碍和学习障碍，类似于AD中所见的症状。因此，Arg-61 apoE对神经退行性变的贡献，特别关注星形胶质细胞功能的作用，将在本提案中进行检查。具体的研究目的是：1）星形胶质细胞代谢对Arg-61 apoE表达水平的直接依赖性，2）Arg-61 apoE星形胶质细胞作为内在组分在Arg-61 apoE表型形成中的可能作用（细胞自主贡献与非细胞自主贡献），3）在CNS损伤的情况下，Arg-61 apoE作为神经变性易感因素的意义。对apoE 4/ Arg-61 apoE机制的深入了解为大多数AD患者的治疗提供了潜在的新的治疗方法。