MODELING ALZHEIMERS DISEASE--BY AMYLOID AND APOE

阿尔茨海默病模型——通过淀粉样蛋白和 APOE

• 批准号: 2517012
• 负责人: RENEE C LEBOEUF
• 金额: $ 26.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517012
• 关键词: Alzheimer's disease; amyloid proteins; apolipoproteins; complementary DNA; cytomegalovirus; disease /disorder model; genetic promoter element; genetically modified animals; genotype; laboratory mouse

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.

描述：（改编自申请人的摘要）AD是一种毁灭性的 一种以进行性记忆丧失为特征的神经变性疾病 和认知功能。 这项研究的长期目标是 阐明β-淀粉样蛋白（Ab）和载脂蛋白的作用 （apo）E在阿尔茨海默病（AD）发病机制中的作用。 可能发挥的作用 对于Ab作为AD发作和进展的标志物或作为AD的病因， 因子在神经炎斑块中的显著积累支持了这一点， 脑血管部位。 遗传学、流行病学和生物化学 越来越多的证据表明，apoE对人的免疫系统发挥同种型特异性作用， AD的发展速度或程度。 调查人员已经 表明淀粉样蛋白C末端区域的过度表达 前体蛋白（APP）导致产生携带Ab的14和15 kDa神经毒性片段在培养的神经元细胞。 此外该 研究人员已经培育出了过量生产这些基因的转基因小鼠， 14和15 Kda碎片。 据说这些老鼠能产生更多的蛋白质 比其他研究者报道的要多。 虽然他们 没有观察到他们的大脑有任何明显的病理变化， 转基因小鼠（长达26个月），已观察到淀粉样蛋白沉积 在这些老鼠的肠道里。 他们假设其他因素 可能是诱导神经病理学变化所必需的 与AD相关，如特定apoE等位基因的表达，或 这些等位基因的数量。 因此，本研究的具体目的 建议：（1）建立过表达人 （2）建立过表达Ab的转基因小鼠， 不同的apoE基因型;和（3）分析AD的转基因小鼠品系 症状 ApoE等位基因特异性cDNA构建体将用 巨细胞病毒启动子系统 人apoE（apoE 3-e3）的过表达 小鼠和apoE 4-e4小鼠）将在缺乏内源性 apoE表达（apoE“敲除”小鼠）， 和育种计划。 这些小鼠将被研究并与小鼠杂交 过表达Ab以确定每种遗传变化的影响， 基因相互作用对AD病理学倾向的影响。 的发展 动物模型表达各种形式的apoE在存在标记的 淀粉样蛋白的表达可能提供了很好的工具， AD的进展、预防和治疗。