APOE AND BETA AMYLOID INTERACTIONS--EFFECTS ON NEUROTOX

描述(改编自申请人的摘要)：这是一份写得很好的 建议研究载脂蛋白E和AD之间关系的应用程序。 尽管最初的研究表明，患者患AD的风险增加 ApoE4基因的多态可能是因为ApoE4提高了 Aβ聚集，这项工作似乎是有缺陷的，因为研究的载脂蛋白E是 无脂，这并不代表人体的正常生理状态 蛋白。调查人员和她的同事随后的工作表明 实际上情况正好相反，即apoE3和E2更好地结合到 Abeta高于apoE4。这表明，其他一些机制可能解释了 ApoE4基因多态患者患AD的风险增加。这个 研究人员现在已经开发出一种Abeta的神经元毒性测试，她说 将在此应用程序的许多研究中使用。这份提案是专门设计的 为了检验以下假设：对Abeta诱导的保护 载脂蛋白E3的神经毒性可能是通过 稳定的apoE3：Abeta复合体的形成及其被apoE受体摄取。 这一假设将通过三个目标进行研究，重点是：(1)载脂蛋白E 对减轻Abeta毒性很重要的受体，(2)apoE/Abeta 络合物刺激或降低毒性；(3)apoE/Abeta摄取Abeta 复合体。

DESCRIPTION (Adapted from applicant's abstract): This is a very well written application that proposes to investigate the relationship between ApoE and AD. Although initial work suggested that the increased risk for AD seen in patients with the apoE4 polymorphism might arise because apo E4 enhances the rate of Abeta aggregation, this work appeared to be flawed because the apoE studied was lipid-free, which does not represent the normal physiological state of the protein. Subsequent work by the investigators and her colleagues suggested that the opposite was actually the case, i.e., that apoE3 and E2 bind better to Abeta than apoE4. This suggests that some other mechanism may account for the increased risk of AD seen in patients with the apoE4 polymorphism. The investigator has now developed a neuronal toxicity assay for Abeta, that she will use in many of the studies in this application. This proposal is designed to test the following hypothesis: that the protection from Abeta-induced neurotoxicity afforded by apoE3 may result from clearance of the peptide via formation of a stable apoE3:Abeta complex and its uptake by apoE receptors. This hypothesis will be investigated via three aims focusing on: (1) the apoE receptors important for attenuating Abeta toxicity, (2) whether apoE/Abeta complexes stimulate or reduce toxicity, and (3) uptake of Abeta in apoE/Abeta complexes.