Modifiers of Beta-Amyloid Metabolism and Deposition

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因，目前是美国第四大死亡原因。AD的特征和诊断是独特的神经病理学改变，包括B-淀粉样蛋白（AB）肽的细胞外沉积。流行病学调查表明，AD是一种复杂的、与年龄相关的疾病，有许多遗传和环境病因。在理解可能改变AD的发作和进展的各种遗传、环境和治疗因素之间的关系方面的主要困难之一是缺乏该疾病的准确和定义的遗传模型。在过去的十年中，许多研究小组已经使用人类AD基因片段产生了转基因小鼠。根据定义，这些模型依赖于关于待表达的基因片段以及用于驱动转基因表达的启动子的某些假设，并且通常维持在不明确的混合遗传背景上，所有这些都使它们用于研究修饰AD表型的因素的效用复杂化。相比之下，我们专注于开发基于基因组的AD小鼠模型（“基因复制”），通过将人类AD基因的完整拷贝引入小鼠的种系中，并且最近在基因组已测序的四种不同小鼠品系中建立了基于基因组的模型。重要的是，我们最近的数据表明，小鼠的遗传背景显着改变了AB肽在这些模型大脑中的代谢和沉积。本提案的具体目的是利用这些独特的小鼠模型，通过以下方式鉴定AB代谢和沉积的体内遗传修饰剂：1）表征四种小鼠品系的年龄相关的分子、生物化学和神经病理学表型。2)基因定位研究，以确定候选基因，调节AB代谢和AB沉积。3)候选基因分析通过基因表达微阵列分析、转基因和分析候选基因在人类AD中的作用。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the fourth major cause of death in the United States. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the B-amyloid (AB)peptide. Epidemiological investigations have demonstrated that AD is a complex, age-related disorder with numerous genetic and environmental etiologies. One of the major difficulties in understanding the relationship between the various genetic, environmental and therapeutic factors that may modify the onset and progression of AD has been the lack of accurate and defined genetic models of the disease. Over the past decade numerous groups have generated transgenic mice using human AD gene fragments. These models, by definition, rely on certain assumptions regarding the fragment of the gene(s) to be expressed as well as the promoter utilized to drive expression of the transgene and are often maintained on ill-defined mixed genetic backgrounds all of which complicate their utility for studying factors that modify AD phenotypes. By contrast, we have focused on developing genomic-based mouse models of AD ("genocopies"), through the introduction of complete copies of human AD genes into the germline of mice and have recently established a genomic-based model in the four different mouse strains whose genomes have been sequenced. Importantly, our recent data demonstrates that genetic background in the mouse dramatically alters both the metabolism and deposition of the AB peptide in the brains of these models. The specific aims of the current proposal are to utilize these unique mouse models to identify in vivo genetic modifiers of AB metabolism and deposition by: 1) Characterization of the age-related molecular, biochemical and neuropathological phenotypes of the four mouse strains. 2) Genetic mapping studies to identify candidate genes that regulate AB metabolism and AB deposition. 3) Candidate gene analysis through gene expression microarray analysis, transgenesis and analysis of the role of the candidate genes in human AD.