Mouse Model of Early Alzheimer's Disease

项目三摘要/摘要 MADRC的中心主题是研究阿尔茨海默病过程的早期特征。在保持 围绕这一主题，该中心旨在了解神经系统功能障碍在出现明显临床症状之前-使用 新的临床分析，先进的神经成像和神经病理学研究专注于淀粉样蛋白阳性， 认知完好的个体。动物模型将是这些早期阶段的另一种重要方法 在我们的知识上存在差距的疾病；不幸的是，尽管动物模型会发展成淀粉样斑块 和/或神经原纤维缠结并可靠地再现AD的分子病理，它们不能再现独一无二的 AD早期发生的解剖学变化的模式。因此，目前还没有AD的动物模型提供一个平台 研究已知发生在人类患者身上的解剖学上受限的病理变化。要解决这个问题 问题是，因此，我们已经产生了一个过度表达人类突变体P301L的转基因小鼠系(RTauEC) Tau主要位于内侧内嗅觉皮质，并在这些神经元中形成缠结，这种模式让人想起 人类阿尔茨海默病的布拉克二期早期。我们将考察这个模型的自然历史，考察时间 缠结、突触丢失和神经元丢失的关系，以解决不可能解决的“鸡和蛋”问题 在人类尸检组织中消除歧义。我们将使用神经系统的行为范式和分子标记 在发病前的早期时间点激活以测试关于神经系统功能去传入的假说 行为异常。RTauEC小鼠的内嗅觉神经元发育异常的tau阳性轴突和改变的轴突 投射，最终失去齿状回的突触终末。该模型还具有可开发性 作为内嗅觉投射靶点的神经元中的tau包涵体存在于齿状回，尽管没有 在这些神经元中表达人tau基因。这被解读为支持这样一种观点，即 病理性tau的跨突触传播。我们已经将带有APP/PS1过表达的rTauEC小鼠 建立内嗅皮层的缠结模型，并在整个皮质形成斑块，类似于人类 许多AD早期病例的病理改变。令人惊讶的是，斑块的增加似乎有力地加速了 缠绕传播表型还会加重轴索营养不良，发展成更严重的神经元性损害 在海马体中。在rTau EC小鼠中，tau的过度表达可以被多西环素调节，类似于一些 各种形式的抗tau疗法。因此，该模型将使我们能够剖析神经系统的详细时间进程 退化，测试定义的神经系统中tau-淀粉样蛋白相互作用的假设，并检查 在疾病过程的不同阶段降低tau的后果。总而言之，这些实验将有所帮助 提供对AD早期阶段的病理生物学的洞察，并强调潜在的机会 在疾病的早期进行治疗干预。

PROJECT THREE SUMMARY/ABSTRACT The central theme of the MADRC is to examine the earliest features of the Alzheimer disease process. In keeping with this theme, the Center aims to understand dysfunction in neural systems prior to overt clinical symptoms - using novel clinical assays, advanced neuroimaging, and neuropathological studies focused on amyloid positive, cognitively intact individuals. Animal models would be an additional important approach to these early phases of disease where there is a gap in our knowledge; unfortunately, although animal models develop amyloid plaques and/or neurofibrillary tangles and reliably reproduce the molecular pathology of AD, they do not reproduce the unique patterns of anatomical changes that occur in early AD. Thus, no current animal models of AD provide a platform to study the anatomically restricted pathological changes that are known to occur in human patients. To address this problem, therefore, we have generated a transgenic mouse line (rTauEC) that over-expresses human mutant P301L tau primarily in the medial entorhinal cortex and develops tangles in those neurons in a pattern that is reminiscent of the early Braak II stage of human AD. We will examine the natural history of this model, examining the temporal relationship of tangles, synapse loss, and neuronal loss, to get at "chicken-and-egg" issues not possible to disambiguate in human autopsy tissue. We will use behavioral paradigms and molecular markers of neural system activation to test hypotheses about functional deafferentation of neural systems at early time points, before onset of behavioral abnormalities. Entorhinal neurons in rTauEC mice develop aberrant tau-filled axons and altered axonal projections, ultimately losing synaptic terminals in the dentate gyrus. This model also has the attribute of developing tau inclusions in the neurons that are the target of the entorhinal projection, in the dentate gyrus, despite not expressing human tau mRNA in those neurons. This has been interpreted as supporting the idea that there is a trans-synaptic propagation of pathological tau. We have crossed the rTauEC mice with APP/PS1 overexpressors to develop a model of tangles in entorhinal cortex and plaques throughout the cortex, analogous to the human pathology of many early cases of AD changes. Surprisingly, the addition of plaques seems to robustly accelerate the tangle propagation phenotype and also exacerbate the axonal dystrophies, developing more severe neuritic lesions in the hippocampus. Tau overexpression can be regulated with doxycycline in the rTau EC mice, mimicking some forms of anti-tau therapies. This model will therefore allow us to dissect a detailed time course of neural system degeneration, test hypotheses about tau-amyloid interactions in a defined neural system, and examine the consequences of reducing tau at various points in the disease process. Together these experiments will help provide insight into the pathobiology of the earliest phases of AD as well as highlight potential opportunities for therapeutic intervention early in the disease.