A conditional mouse model of Alzheimer's disease

描述(由申请人提供)： 对阿尔茨海默病(AD)病因的理解和对潜在治疗方式的评估严重依赖于该疾病的动物模型。目前非诱导性AD动物模型的应用受到限制，原因是1)转基因从出生起就过度表达可能影响AD样病理的发育效应，以及2)无法在成年动物中关闭转基因表达以确定转基因失活对AD样病理的影响。这项建议的重点是通过建立在四环素(TAT)调控系统下过度表达突变的人淀粉样前体蛋白(MhAPP)的AD转基因小鼠模型来解决这些问题。在特定目标1中，将产生并验证包含Teto响应启动子和突变型人APP cDNA的构建体(Teto-mhAPP)。在特定目标2中，将产生在TAT调控下在前脑有条件表达mhAPP的小鼠(命名为Tet/mhAPP)。特定目的3将研究TET/mhAPP小鼠在出生后诱导转基因表达的AD样病理动力学。最后，在特定目标4中，将通过阻断已建立AD样病理的老年小鼠mhAPP的表达来研究逆转AD样病理的可能性。

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.