A conditional mouse model of Alzheimer's disease

描述（由申请人提供）： 对阿尔茨海默病（AD）病因学的了解和潜在治疗方式的评估很大程度上取决于该疾病的动物模型。目前不可诱导的AD动物模型的实用性是有限的，因为1）从出生起转基因过度表达可能对发育产生影响，这可能影响AD样病理学，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样病理学的影响。该提案的重点是通过建立 AD 转基因小鼠模型来解决这些问题，该模型在四环素 (tat) 调节系统下过表达突变型人类淀粉样前体蛋白 (mhAPP)。在具体目标 1 中，将生成并验证包含 tetO 响应启动子和突变人 APP cDNA (tetO-mhAPP) 的构建体。在具体目标2中，将产生在tat调节控制下在前脑中有条件表达mhAPP的小鼠（指定为Tet/mhAPP）。具体目标 3 将研究 Tet/mhAPP 小鼠中 AD 样病理学的动力学，其中转基因表达在出生后被诱导。最后，在具体目标 4 中，将通过阻断已形成 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。

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.