The role of astrocytes in apoE4 related neurodegeneration.

阿尔茨海默病（AD）是一种神经退行性疾病，在后工业化世界发病率越来越高。遗传原因以及不同的易感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的主要遗传危险因素是载脂蛋白（apo） E4，载脂蛋白E4是人类3种载脂蛋白e亚型之一，65-80%的AD患者携带载脂蛋白E4。这种关联的分子机制尚不清楚，目前也没有基于apoE4易感性的治疗方法。来自旧金山Gladstone研究所的Weisgraber等人确定了apoE4异构体结构的独特变化，这些变化预计会影响其功能：其中之一是导致紧凑蛋白质结构的结构域相互作用。该小组开发了一种选择性特异性区域相互作用的小鼠模型，Arg-61 apoE小鼠（本提案中的模型系统）。该模型的研究表明，这些小鼠的结构域相互作用导致内质网应激水平升高，并诱导星形胶质细胞功能障碍，从而可能导致神经元修复和维持功能受损。动物表现出与阿尔茨海默病相似的认知功能障碍和学习障碍。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，将在本提案中进行研究。具体的研究目标将是1)星形胶质细胞代谢对Arg-61 apoE表达水平的直接依赖，2)Arg-61 apoE星形胶质细胞作为Arg-61 apoE表型发展的内在成分的可能作用（细胞自主与非细胞自主贡献）3)Arg-61 apoE作为中枢神经系统损伤时神经退行性变的易感因素的意义。apoE4/ Arg-61 apoE机制的深入研究为大多数AD患者的治疗开辟了新的治疗途径。

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.