Trangenic Mouse Model of Alzheimer's Disease

阿尔茨海默病转基因小鼠模型

• 批准号: 6912777
• 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/6912777
• 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（由申请人提供）：虽然已经开发了几种转基因小鼠品系作为 AB 淀粉样变性模型，但它们都没有完全显示出过度磷酸化的 tau 内含物和突触损失，而这些是临床阿尔茨海默病 (AD) 神经病理学的重要标志。 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佳证据是发现一些斑块被营养不良的神经突（DN）包围。因此，为了研究观察到的与 APP 过度表达相关的神经变性是否依赖于 tau 的存在，我们将过度表达人类 APP 的小鼠（TG2576 转基因小鼠）与我们的 tau 敲除小鼠（muTau-/-）交配。 在本提案中，我们打算通过表征 tau 敲除背景下 APP 过表达转基因小鼠的组织学和行为表型，并将其与野生型动物和小鼠和人源化 tau 背景下过表达 APP 的小鼠进行比较，探讨 tau 在 AD 病理学中的作用。 临床证据表明创伤性脑损伤与 AD 的发展之间存在关联。 有证据表明，这可以在 APP 过度表达的小鼠中进行建模，其中轻度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生存模型，其中机械通气的动物被置于严格的生理控制下，并接受对闭合头骨的气动冲击，产生比之前描述的更严重的脑损伤。 我们将用它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 的发生率较低，因此该领域正在进行多项临床试验。 我们还发现，服用辛伐他汀可以减少创伤性脑损伤后的功能缺陷。 基于此，我们将施用辛伐他汀以确定这是否可以改善转基因系中创伤性脑损伤后的组织学或功能结果。 最终，这可能会带来可用于临床试验的新型治疗策略。

项目成果

Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease.

• DOI: 10.1016/j.neuroscience.2010.04.037
• 发表时间: 2010-08-11
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Dawson, H. N.;Cantillana, V.;Jansen, M.;Wang, H.;Vitek, M. P.;Wilcock, D. M.;Lynch, J. R.;Laskowitz, D. T.
• 通讯作者: Laskowitz, D. T.