TRANSGENIC RAT MODELS OF ALZHEIMER'S DISEASE

阿尔茨海默病转基因大鼠模型

• 批准号: 6497194
• 负责人: Victoria L Herrera
• 金额: $ 36.21万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497194
• 关键词: Alzheimer's disease; amyloid proteins; amyloidosis; atherosclerosis; behavior test; behavioral /social science research tag; complement; disease /disorder model; genetically modified animals; hippocampus; hypercholesterolemia; laboratory rat; memory; model design /development; neurofibrillary tangles; neuropsychology

Animal models are proven investigative tools for study of complex human diseases such as Alzheimer s Disease (AD) and atherosclerosis. Trangenic and bigenic mouse models for presenilin-1 (PS1) and amyloid precursor protein (APP) human gene variants have been instrumental in delineating their roles in AD pathogenesis. However, to date these mouse models have not exhibited key AD pathology such as neurofibrillary tangles, neuronal loss and AD-associated cognitive/neurobehavioral deficits. We hypothesize that a more phenotypically robust and experimentally accessible model of Alzheimer s disease will be obtained in the rat based on key observations: a) rat ApoE is more homologous to human ApoE4 compared with mouse; b) rat complement, like the human has greater levels compared with the mouse and might be a key determinant to the development of neurofibrillary tangles; c) neurobehavioral studies assessing aging and hippocampal-specific learning and memory deficits have been validated in the rat; d) the size of the rat allows lesioning and imaging studies; f) the more robust atherosclerotic phenotype in transgenic rats compared with mice given the same human cholesteryl ester transfer (hCETP) transgene indicates valid modeling for complex diseases. This proposal focuses on the following specific aims. (1) Develop three key inbred Fischer 344 rat AD models with the highest probability for a robust AD phenotype: a) homozygous high-expresser of mutant human APPSWE AD gene, TgAPP, b) homozygous bigenic with both mutant human PSIM146L and hAPPSWE, 2TG[PS1xAPP], and a trigenic rat model, 3Tg]PS1 x APAP x hCETP], which imposes, if not test, hypercholesterolemia-induced exacerbaytion of amyloidogenic APP processing in vivo. (2) Investigate the degree of cognitive deficits in the combinational transgenic rat AD models by measuring hippocampal-dependent working memory and spatial learning and memory at 12, 18, 24 months. 3) Correlate observed hippocampal-dependent neurobehavioral alterations with AD- associated neuropathological alterations at 12, 18, and 24 months. (4) Correlate key neurobehavioral and neuropathological alterations with molecular and cellular markers of AD pathogenesis at 12, 18, and 24 months. Comparative analysis of the proposed rat models will not only address an accessible AD model for mechanistic dissection and therapy development, but also provide insight into the role of complement- and hypercholesterolemia-mediated disease paradigms in AD pathogenesis.

动物模型是研究阿尔茨海默病 (AD) 和动脉粥样硬化等复杂人类疾病的行之有效的研究工具。 早老素 1 (PS1) 和淀粉样前体蛋白 (APP) 人类基因变异的转基因和双基因小鼠模型有助于描述它们在 AD 发病机制中的作用。 然而，迄今为止，这些小鼠模型尚未表现出关键的 AD 病理学，例如神经原纤维缠结、神经元丢失和 AD 相关的认知/神经行为缺陷。 基于以下关键观察结果，我们假设将在大鼠中获得表型更稳健、实验上更容易获得的阿尔茨海默氏病模型：a) 与小鼠相比，大鼠 ApoE 与人 ApoE4 更同源； b) 大鼠补体，就像人类一样，与小鼠相比，其水平更高，可能是神经原纤维缠结发展的关键决定因素； c) 评估衰老和海马特异性学习和记忆缺陷的神经行为研究已在大鼠中得到验证； d) 大鼠的大小允许进行损伤和成像研究； f) 与接受相同人胆固醇酯转移 (hCETP) 转基因的小鼠相比，转基因大鼠的动脉粥样硬化表型更强大，表明复杂疾病的模型是有效的。 该提案重点关注以下具体目标。 (1) 开发三种关键的近交 Fischer 344 大鼠 AD 模型，其具有最高的稳健 AD 表型概率：a) 突变型人类 APPSWE AD 基因 TgAPP 的纯合高表达者，b) 具有突变型人类 PSIM146L 和 hAPPSWE 的纯合双基因，2TG [PS1xAPP]，以及三基因大鼠模型，3Tg]PS1 x APAP x hCETP]，如果不进行测试，高胆固醇血症会引起体内淀粉样蛋白 APP 加工的加剧。 (2)通过测量12、18、24个月时的海马依赖性工作记忆和空间学习记忆来研究组合转基因大鼠AD模型的认知缺陷程度。 3) 将 12、18 和 24 个月时观察到的海马依赖性神经行为改变与 AD 相关神经病理学改变相关联。 (4) 将 12、18 和 24 个月时的关键神经行为和神经病理学改变与 AD 发病机制的分子和细胞标志物相关联。 对所提出的大鼠模型的比较分析不仅将解决可用于机械解剖和治疗开发的 AD 模型，而且还可以深入了解补体和高胆固醇血症介导的疾病范式在 AD 发病机制中的作用。