Seeded models of AD pathology

项目摘要 阿尔茨海默氏病（AD）现在被认为是一种具有长的初始阶段的疾病，在该疾病中， 病理学异常在第一个疾病症状出现之前很久就出现了。第一个病理事件是 A肽沉积在弥漫性淀粉样蛋白沉积物和称为老年斑的结构中。这些 变化可能在症状出现前约20年开始发生。在死亡时，表现出 只有淀粉样病变在很大程度上认知正常。表现出轻度认知障碍的个体， 死亡时间可能表现出一系列的病理特征，但一个大的子集显示丰富的淀粉样蛋白病理 以及一定水平的异常tau病理学（范围从磷酸化tau的积累到神经元损伤）。 缠结）。表现出更严重的认知障碍、符合AD诊断的临床标准的个体， 在尸检时总是具有显著的tau病理学沿着淀粉样蛋白（严重程度更易变）。这 人类数据令人信服地认为，淀粉样蛋白的沉积以某种方式诱导了继发性 Tau的错误折叠。然而，无法模拟从主要淀粉样蛋白病理学到淀粉样蛋白病理学的阶段性转变， 淀粉样蛋白和tau蛋白病阻碍了我们确定表观遗传学基础的分子机制的能力， AD中tau病理学的继发诱导。 迄今为止，已经有多次尝试来产生复制AD的这一重要特征的模型 使用各种转基因和基因靶向方法。转基因模型的一个主要缺点是 通常需要表达高水平的转基因，以提高聚集的水平， 蛋白质含量高到足以自发地形成纤维状聚集。有了R21，我们希望 确定是否在表达低得多的突变型人APP的小鼠中接种淀粉样蛋白病理 和Tau将产生淀粉样蛋白先于Tau病理出现的模型， 完全依赖于淀粉样蛋白病理的诱导和严重程度（如在 人类）。我们提出，我们可以通过产生小鼠来产生能够实现这一目标的宿主， 表达低水平的突变型人APP（淀粉样蛋白沉积在18个月时首次出现）和突变型人APP（淀粉样蛋白沉积在18个月时首次出现）。 tau（无病理学）。我们假设，在共表达这些蛋白的小鼠中， 转基因将创建一个模型，其中淀粉样蛋白沉积特别加速，然后是二次沉积 诱导tau病理学。我们建议，如果成功的话，这些模型可以用来更好地理解 驱动主要淀粉样变性向淀粉样蛋白与tau病理之间转变的机制。

Project Summary Alzheimer's Disease (AD) is now recognized as a disorder with a long incipient phase in which a myriad of pathologic abnormalities occur long before the first disease symptoms appear. The first pathologic event is the deposition of A¿ peptides in deposits of diffuse amyloid and in structures referred to as senile plaques. These changes may begin to occur some 20 years before the onset of symptoms. At death, individuals that exhibit only amyloid pathology are largely cognitively normal. Individuals that exhibit mild cognitive impairment at the time of death may exhibit a range of pathologic features, but a large subset show abundant amyloid pathology and some level of abnormal tau pathology (ranging from accumulation of phosphorylated tau to neurofibrillary tangles). Individuals that exhibit more severe cognitive impairment, meeting clinical criteria for diagnosis of AD, at autopsy will invariably have significant tau pathology along with amyloid (more variable in severity). This human data argues persuasively that the deposition of amyloid in some manner induces a secondary misfolding of tau. However, the inability to model the staged transition from primarily amyloid pathology to amyloid and tauopathy has impeded our ability to define the molecular mechanisms that underlie the apparent secondary induction of tau pathology in AD. To date there have been multiple attempts to produce models that replicate this important feature of AD using various transgenic and gene-targeting approaches. A key drawback to the transgenic models has been that often there is a need to express high levels of a transgene in order to raise the levels of aggregating proteins high enough that they will spontaneously seed fibrillar aggregation. With this R21, we seek to determine whether seeding amyloid pathology in mice that express much lower levels of mutant human APP and Tau will produce models in which amyloid precedes the appearance of tau pathology in a manner that is completely dependent upon the induction and severity of the amyloid pathology (as appears to occur in humans). We propose that we can generate hosts that would accomplish this goal by generating mice that co- express low levels of mutant human APP (amyloid deposition first appears at 18 months) and mutant human tau (no pathology). We hypothesize that seeded induction of amyloid deposition in mice that co-express these transgenes will create a model in which amyloid deposition in specifically accelerated, followed by a secondary induction of tau pathology. We propose that if successful, such models could be used to better understand the mechanisms that drive the transition between primarily amyloidosis to amyloid with tau pathology.