Trangenic Mouse Model of Alzheimer's Disease

描述（由申请人提供）：虽然已经开发了几种转基因小鼠菌株作为AB淀粉样变模型，但它们都没有完全显示出临床阿尔茨海默病（AD）神经病理学的重要标志-过度磷酸化的tau内含物和突触丧失。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，为了研究与APP过表达相关的神经退行性变是否依赖于tau的存在，我们将过表达人类APP的小鼠（TG2576转基因小鼠）与tau敲除小鼠（muTau-/-）进行了交配。在本研究中，我们打算通过描述tau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小鼠在小鼠和人源化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AD的发展之间存在关联。有证据表明，这可能在APP过表达小鼠中建模，轻度创伤性脑损伤促进a沉积和认知缺陷。我们最近描述了一个创伤性脑损伤小鼠生存模型，在该模型中，机械通气的动物被置于严格的生理控制下，并对封闭的颅骨进行气动冲击，产生比先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。

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.