Mouse Model of Early Alzheimer's Disease

项目三概要/摘要 MADRC的中心主题是研究阿尔茨海默病过程的最早特征。一致 在这个主题下，该中心的目标是了解神经系统功能障碍在明显的临床症状之前-使用 新的临床分析、先进的神经成像和神经病理学研究集中在淀粉样蛋白阳性， 认知完整的个体。动物模型将是这些早期阶段的另一个重要方法。 我们的知识存在差距的疾病;不幸的是，尽管动物模型产生淀粉样斑块， 和/或神经元缠结并可靠地再现AD的分子病理学，但它们不再现AD的独特病理学特征。 AD早期发生的解剖学变化模式。因此，目前没有AD的动物模型提供平台， 研究已知在人类患者中发生的解剖学限制的病理变化。为了解决这个 因此，我们已经产生了过表达人突变体P301 L的转基因小鼠系（rTauEC tau蛋白主要存在于内侧内嗅皮质中，并在这些神经元中以一种模式发展缠结， 人类AD的早期Braak II阶段。我们将研究这个模型的自然历史， 缠结、突触丢失和神经元丢失之间的关系，要解决“先有鸡还是先有蛋”的问题， 在人体解剖组织中的意义我们将使用行为范例和神经系统的分子标记 激活，以测试有关神经系统功能性传入阻滞的假设，在发病前的早期时间点， 行为异常rTauEC小鼠中的内嗅神经元发育异常的tau填充轴突和改变的轴突 突起，最终失去齿状回中的突触末端。这种模式也具有发展的属性 在齿状回中，作为内嗅投射靶点的神经元中的tau内含物，尽管没有 在这些神经元中表达人类tau mRNA。这被解释为支持这样一种观点，即 病理性tau的跨突触传播。我们将rTauEC小鼠与APP/PS1过表达者杂交， 开发一个内嗅皮层缠结和整个皮层斑块的模型，类似于人类 许多早期AD病例的病理改变。令人惊讶的是，斑块的加入似乎有力地加速了 缠结传播表型，也加剧了轴突营养不良，发展更严重的神经炎病变 在海马区。在rTau EC小鼠中，Tau过表达可以用多西环素调节，模拟了一些 抗tau治疗的形式。因此，这个模型将允许我们解剖神经系统的详细时间过程 变性，测试关于在定义的神经系统中tau-淀粉样蛋白相互作用的假设，并检查 在疾病过程中的各个点减少tau的后果。这些实验将有助于 提供对AD最早阶段的病理生物学的深入了解，并突出潜在的机会， 在疾病早期进行治疗干预。

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.