GENETIC MODIFIERS OF ALZHEIMER'S DISEASE ANIMAL MODELS

阿尔茨海默病动物模型的基因修饰

• 批准号: 6611076
• 负责人: Bruce T Lamb
• 金额: $ 20.26万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611076
• 关键词: Alzheimer's disease; apolipoprotein E; artificial chromosomes; disease /disorder model; gene dosage; gene targeting; genetic models; genetic susceptibility; genetically modified animals; laboratory mouse; learning disorders; memory disorders; model design /development; neurogenetics; neuropathology

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the fourth major cause of death in the developed world after heart disease, cancer and stroke. AD is strongly influenced by genetics, with current estimates suggesting that greater than 40% of all AD cases are familial (FAD). Genetic investigations have demonstrated that AD is a heterogeneous disorder with several known etiologies including: dosage imbalance for chromosome 21 as occurs in Down syndrome (DS); mutations in the amyloid precursor protein (APP) gene on chromosome 21, the presenilin-1 (PS-1) gene on chromosome 14 and the presenilin-2 (PS-2) gene on chromosome 1 in autosomal dominant early-onset FAD; and inheritance of distinct alpha-2 microglobulin and apolipoprotein E (ApoE) gene alleles on chromosome 12 and 19, respectively, as significant genetic risk factors for late-onset FAD. Additional genetic risk factors for AD are certain to exist. A pathologic hallmark in the brains of individuals with AD is deposits of the beta- amyloid (Abeta) peptide in the parenchyma of amygdala, hippocampus and neocortex. One of the major difficulties in studying the mechanism(s) of Abeta deposition and its impact on AD-related neuropathology, behavior and physiology is the paucity of accurate animal models. To establish an accurate genetic model for AD, we have focused on introducing entire genomic copies of either wild-type (wt) or mutant human APP and PS-1 genes carried on yeast artificial chromosomes (YACs) into the mouse germline and have recently demonstrated that a threshold into the molecular and mechanisms of the disease. The specific aims of the current proposal are to examine the effect of specific human AD genetic risk factors, namely dosage imbalance for genes on chromosome 21 (in the Ts65Dn mouse model of DS) and the various ApoE alleles (in ApoE knock-in mice), across the lifespan of APP YAC transgenic mice on: 1) Localization and timing of Abeta deposition and other structural neuropathology. 2) Learning and memory deficits characteristic of individuals with AD.

阿尔茨海默病（AD）是老年痴呆症最常见的原因，现在是发达国家心脏病、癌症和中风之后的第四大死亡原因。AD受到遗传学的强烈影响，目前的估计表明，超过40%的AD病例是家族性的（FAD）。遗传学研究表明，AD是一种异质性疾病，具有几种已知的病因，包括：如唐氏综合征（Down syndrome，DS）中发生的21号染色体剂量失衡;常染色体显性早发性FAD中21号染色体上的淀粉样前体蛋白（amyloid precursor protein，APP）基因、14号染色体上的早老素-1（presenilin-1，PS-1）基因和1号染色体上的早老素-2（presenilin-2，PS-2）基因的突变;以及分别位于12号和19号染色体上的不同α-2微球蛋白和载脂蛋白E（ApoE）基因等位基因的遗传，作为晚发型FAD的重要遗传风险因素。AD的其他遗传风险因素肯定存在。患有AD的个体的脑中的病理标志是β-淀粉样蛋白（Abeta）肽在杏仁核、海马和新皮质的实质中的沉积。研究Abeta沉积的机制及其对AD相关神经病理学、行为学和生理学的影响的主要困难之一是缺乏准确的动物模型。为了建立AD的精确遗传模型，我们专注于将酵母人工染色体（YAC）上携带的野生型（wt）或突变型人类APP和PS-1基因的全基因组拷贝引入小鼠种系中，并且最近证明了该疾病的分子和机制的阈值。当前提案的具体目的是检查特定人类AD遗传风险因素的影响，即21号染色体上的基因（在DS的Ts 65 Dn小鼠模型中）和各种ApoE等位基因（在ApoE敲入小鼠中）的剂量失衡，在APP YAC转基因小鼠的整个寿命中对：1）Abeta沉积和其他结构性神经病理学的定位和时间。2)AD患者的学习和记忆缺陷特征。