Trangenic Mouse Model of Alzheimer's Disease

描述（由申请人提供）：尽管已经开发了几种转基因小鼠品系作为AB淀粉样变性的模型，但它们中没有一种完全显示出过度磷酸化的tau包涵体和突触丢失，这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过表达相关的神经变性是否依赖于tau的存在，我们将过表达人APP的小鼠（TG 2576转基因小鼠）与我们的tau敲除小鼠（muTau-/-）交配。 在这项提案中，我们打算探索tau在AD病理学中的作用，通过表征在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在鼠和人源化tau背景下过表达APP的小鼠进行比较。 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，这可能在APP过度表达小鼠中建模，其中轻度脑外伤促进了A。沉积和认知缺陷。 我们最近的特点是创伤性脑损伤的小鼠存活模型，其中机械通气的动物被置于严格的生理控制下，并接受对闭合的颅骨的气动冲击，产生比以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）的患者发生AD的发病率较低，导致该领域的几项正在进行的临床试验。 我们还发现，辛伐他汀的管理减少创伤性脑损伤后的功能缺陷。 基于此，我们将给予辛伐他汀，以确定这是否改善了转基因系创伤性脑损伤后的组织学或功能结局。 最终，这可能会导致新的治疗策略，可用于临床试验。

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.