MODELING ALZHEIMERS DISEASE--BY AMYLOID AND APOE

描述：(改编自申请者的摘要)广告是一个毁灭性的 以进行性记忆丧失为特征的神经退行性疾病 和认知功能。这项研究的长期目标是 阐明β-淀粉样蛋白和载脂蛋白的作用 (Apo)E在阿尔茨海默病(AD)发病中的作用一个可能的角色 抗体作为AD发病和进展的标志或作为致病因素 因子由其在神经炎斑块中的显著积聚和 脑血管部位。遗传、流行病学和生化 越来越多的证据表明，载脂蛋白E对 AD的发展速度或程度。调查人员已经 证实了淀粉样蛋白C-末端区域的过度表达 前体蛋白(APP)导致抗体14和15的产生 培养神经细胞中的KDA神经毒性片段。此外， 研究人员已经培育出了过量繁殖这些基因的转基因小鼠。 14个和15个KDA片段。据说这些老鼠能产生更多的蛋白质。 大脑中的产物比其他研究人员报告的要多。尽管他们 在他们的大脑中没有观察到任何明显的病理变化 转基因小鼠(长达26个月)，观察到淀粉样蛋白沉积 在这些小鼠的肠道里。他们假设其他因素 可能是诱导神经病变所必需的 与AD相关，如特定载脂蛋白E等位基因的表达，或 这些等位基因的数量。因此，这项研究的具体目的是 建议：(1)建立高表达人类基因的转基因小鼠 APOE3和apoE4；(2)建立高表达抗体的转基因小鼠 不同载脂蛋白E基因类型；以及(3)分析AD转基因小鼠品系 症状。APOE等位基因特定的CDNA构建将与 巨细胞病毒启动子系统。人载脂蛋白E(apoE3-E3)的过表达 小鼠和apoE4-e4小鼠)将建立在内源性缺乏的小鼠身上 联合转基因表达载脂蛋白E(apoE“基因敲除”小鼠) 和繁育计划。这些小鼠将被研究并与小鼠杂交 过量表达抗体以确定每个基因变化的影响和 基因交互作用对AD病理倾向的影响。的发展。 在有标记的情况下表达不同形式载脂蛋白E的动物模型 淀粉样蛋白的表达可能提供了很好的工具来研究 AD的进展、预防和治疗。

DESCRIPTION: (adapted from Applicant's Abstract) AD is a devastating neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. The long-term goal of this research is to elucidate the role of beta-amyloid protein (Ab) and apolipoprotein (apo)E in the pathogenesis of Alzheimer's disease (AD). A possible role for Ab as either a marker for AD onset and progression or as a causative factor is supported by its marked accumulation in neuritic plaques and cerebrovascular sites. Genetic, epidemiological, and biochemical evidence is mounting that apoE exerts an isoform specific-effect on the rate or extent of development of AD. The investigators already demonstrated that overexpression of a C-terminal region of amyloid precursor protein (APP) leads to the production of Ab-bearing 14 and 15 kDa neurotoxic fragments in cultured neuronal cells. In addition, the investigators have already created transgenic mice that overproduce these 14 and 15 Kda fragments. These mice are said to produce more protein product in brain than reported by other investigators. Although they have not observed any obvious pathological changes in the brains of their transgenic mice (up to 26 months), amyloid deposits have been observed in the intestines of these mice. They hypothesize that other factors may be necessary for the induction of neuropathological changes associated with AD, such as expression of specific apoE alleles, or quantities of these alleles. Thus, the Specific Aims of this research proposal are to: (1) establish transgenic mice overexpressing human apoE3 and apoE4; (2) establish transgenic mice overexpressing Ab with different apoE genotypes; and (3) analyze transgenic mouse lines for AD symptoms. ApoE allele specific CDNA constructs will be made with a cytomegalovirus promoter system. Overexpression of human apoE (apoE3-e3 mice and apoE4-e4 mice) will be established in mice lacking endogenous apoE expression (apoE "knock-out" mice) by a combination of transgenic and breeding schemes. These mice will be studied and crossed to mice overexpressing Ab to determine the effects of each genetic change and gene interactions on the propensity of AD pathology. The development of animal models expressing various forms of apoE in the presence of marked amyloid expression may provide excellent tools in which to study the progression, prevention, and treatment of AD.