Trangenic Mouse Model of Alzheimer's Disease

阿尔茨海默病转基因小鼠模型

• 批准号: 6757211
• 负责人: JOHN R LYNCH
• 金额: $ 18.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757211
• 关键词: Alzheimer' s disease; aging; brain injury; cognition disorders; disease /disorder model; gene targeting; genetically modified animals; immunocytochemistry; laboratory mouse; neural degeneration; psychomotor function; simvastatin; tau proteins; western blottings

DESCRIPTION (provided by applicant): Although several transgenic mouse strains have been developed as models of AB amyloidosis, none of them fully display the hyperphosphorylated tau inclusions and synaptic loss that are important hallmarks of clinical Alzheimer's disease (AD) neuropathology. The best evidence that neurodegeneration occurs in these murine models of amyloid overexpression is the finding that some plaques are surrounded by dystrophic neurites (DNs). Thus, to investigate whether the observed neurodegeneration associated with APP overexpression is dependent on the presence of tau, we mated mice overexpressing human APP (TG2576 transgenic mouse) to our tau knockout mouse (muTau-/-). In this proposal, we intend to explore the role of tau in AD pathology by characterizing the histologic and behavioral phenotype of APP overexpressing transgenic mice in a tau knockout background and comparing this to wild type animals and mice overexpressing APP in a murine and humanized tau background. Clinical evidence suggests an association between traumatic brain injury and development of AD. Evidence suggests that this may be modeled in APP overexpressing mice, in which a mild traumatic brain injury promoted A. deposition and cognitive deficits. We have recently characterized a murine survival model of traumatic brain injury in which mechanically ventilated animals are placed under tight physiological controls and receive a pneumatic impact against the closed skull, producing a more severe brain injury than previously described. We will use this to accelerate the motor and cognitive deficits in these transgenic mice. Clinical observations also suggest that patients on statins (HMG CoA reductase inhibitors) have a lower incidence of developing AD, leading to several ongoing clinical trials in this area. We have also found that administration of simvastatin reduced functional deficits following traumatic brain injury. Based on this, we will administer simvastatin to determine whether this improves the histological or functional outcome following traumatic brain injury in the transgenic lines. Ultimately, this may lead to novel therapeutic strategies that are translatable for use in clinical trials.

描述(申请人提供)：尽管已经开发了几个转基因小鼠品系作为AB淀粉样变性的模型，但没有一个品系完全显示出过度磷酸化的tau包涵体和突触丢失，这些都是临床阿尔茨海默病(AD)神经病理的重要特征。在这些淀粉样蛋白过度表达的小鼠模型中，发生神经变性的最好证据是发现一些斑块被营养不良神经突起(DN)包围。因此，为了研究观察到的与APP过度表达相关的神经退行性变是否依赖于tau的存在，我们将过度表达人APP的小鼠(Tg2576转基因小鼠)与tau基因敲除小鼠(muTau-/-)交配。在这项研究中，我们打算通过鉴定tau基因敲除背景下过表达APP的转基因小鼠的组织学和行为表型，并将其与野生型动物和在鼠类和人源化tau背景下过表达APP的小鼠进行比较，来探讨tau在AD病理中的作用。临床证据表明，创伤性脑损伤与阿尔茨海默病的发生有关。有证据表明，这可能是在APP过度表达的小鼠身上建立的模型，在小鼠中，轻微的创伤性脑损伤促进了A沉积和认知缺陷。我们最近描述了一种创伤性脑损伤的小鼠存活模型，在该模型中，机械通风的动物被置于严格的生理控制下，并受到闭合的头骨的气动冲击，产生比先前描述的更严重的脑损伤。我们将利用这一点来加速这些转基因小鼠的运动和认知缺陷。 临床观察还表明，服用他汀类药物(HMG CoA还原酶抑制剂)的患者患AD的几率较低，导致这一领域的几项正在进行的临床试验。我们还发现，给予辛伐他汀可减少创伤性脑损伤后的功能障碍。在此基础上，我们将给予辛伐他汀，以确定这是否改善了转基因品系中创伤性脑损伤后的组织学或功能结果。最终，这可能导致可翻译用于临床试验的新的治疗策略。