A conditional mouse model of Alzheimer's disease

阿尔茨海默病的条件小鼠模型

• 批准号: 6694189
• 负责人: TERRENCE C TOWN
• 金额: $ 3.97万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2006-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6694189
• 关键词: Alzheimer's disease; amyloid proteins; calmodulin dependent protein kinase; disease /disorder model; gene expression; genetic promoter element; genetically modified animals; immunocytochemistry; laboratory mouse; model design /development; neuropathology; postdoctoral investigator; tetracyclines; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): An understanding of Alzheimer's disease (AD) etiology and evaluation of potential therapeutic modalities is critically dependent upon animal models of the disease. The utility of current non-inducible animal models of AD is limited, due to 1) possible developmental effects of transgene overexpression from birth which could influence AD-like pathology, and 2) inability to turn transgene expression "off" in adult animals to determine the effect of transgene inactivation on AD-like pathology. The focus of this proposal is to address these issues by establishing a transgenic mouse model of AD that overexpresses mutant human amyloid precursor protein (mhAPP) under the tetracycline (tat) regulated system. In specific aim 1, a construct containing a tetO responsive promoter and a mutant human APP cDNA (tetO-mhAPP) will be generated and validated. In specific aim 2, mice (designated Tet/mhAPP) that conditionally express mhAPP in the forebrain under tat regulatory control will be generated. Specific aim 3 will investigate the kinetics of AD-like pathology in Tet/mhAPP mice in which transgene expression is induced postnatally. Finally, in specific aim 4, possible reversal of AD-like pathology will be examined by blocking mhAPP expression in aged mice with established AD-like pathology.

描述（由申请人提供）： 了解阿尔茨海默病（AD）的病因和评价潜在的治疗方式是严重依赖于动物模型的疾病。目前AD的非诱导型动物模型的实用性有限，这是由于1）从出生起转基因过表达的可能发育效应，其可能影响AD样病理学，和2）不能在成年动物中“关闭”转基因表达以确定转基因失活对AD样病理学的影响。本提案的重点是通过建立在四环素（达特）调节系统下过表达突变型人淀粉样前体蛋白（mhAPP）的AD转基因小鼠模型来解决这些问题。在具体目标1中，将产生并验证含有tetO响应性启动子和突变型人APP cDNA（tetO-mhAPP）的构建体。在具体的目的2中，将产生在达特调节控制下在前脑中条件性表达mhAPP的小鼠（命名为泰特/mhAPP）。具体目标3将研究出生后诱导转基因表达的泰特/mhAPP小鼠中AD样病理学的动力学。最后，在具体目标4中，将通过阻断具有确定的AD样病理的老年小鼠中的mhAPP表达来检查AD样病理的可能逆转。