Mouse Model of Early Alzheimer's Disease

早期阿尔茨海默病小鼠模型

• 批准号: 9251148
• 负责人: BRADLEY T. HYMAN
• 金额: $ 22.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9251148
• 关键词: AD pathology; APP-PS1; Address; Alzheimer' s Disease; Amyloid; Anatomy; Animal Disease Models; Animal Model; Array tomography; Autopsy; Axon; Behavioral; Behavioral Assay; Behavioral Paradigm; Biological Assay; Cells; Characteristics; Chickens; Clinical; Cognitive; Data; Deafferentation procedure; Deposition; Development; Disease; Disease model; Doxycycline; Early Intervention; Elements; Functional disorder; Grant; Hippocampus (Brain); Human; Human Pathology; Individual; Investigation; Knowledge; Lead; Lesion; Massachusetts; Medial; Memory impairment; Messenger RNA; Modeling; Molecular; Mus; Natural History; Neurofibrillary Tangles; Neuronal Plasticity; Neurons; Pathologic; Patients; Pattern; Phase; Phenotype; Presynaptic Terminals; Process; Research; Resources; Senile Plaques; Structure of molecular layer of cerebellar cortex; Symptoms; Synapses; System; Tauopathies; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Transgenes; Transgenic Mice; conditioned fear; dentate gyrus; egg; entorhinal cortex; experimental study; extracellular; granule cell; human disease; human tissue; in vivo; insight; molecular marker; molecular pathology; mouse model; mutant; neuroimaging; neuron loss; neuropathology; novel; overexpression; relating to nervous system; response; tau Proteins; transgene expression

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.

项目三摘要/摘要 MADRC的中心主题是检查阿尔茨海默氏病过程的最早特征。保持 以此为主题，该中心旨在在明显的临床症状之前了解神经系统的功能障碍 - 使用 新型临床测定，晚期神经影像学和神经病理学研究的重点是淀粉样蛋白阳性， 认知完整的人。动物模型将是针对这些早期阶段的其他重要方法 疾病我们所知存在差距；不幸的是，尽管动物模型发展了淀粉样斑块 和/或神经原纤维缠结，可靠地再现AD的分子病理，它们不重现独特的 AD早期发生解剖变化的模式。因此，目前没有广告模型为 研究人类患者已知发生的解剖学限制病理变化。解决这个问题 因此，我们已经生成了过表达人突变体P301L的转基因小鼠系（RTAUEC） tau主要在内侧肠道皮质中，并以一种让人联想到的神经元中的缠结 人类广告的早期Braak II阶段。我们将检查该模型的自然历史，检查时间范围 缠结，突触丧失和神经元损失的关系，无法解决“鸡肉和蛋”的问题 在人体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 激活以测试关于早期神经系统功能剥离的假设， 行为异常。 RTAUEC小鼠中的内嗅神经元出现异常充满tau的轴突并改变了轴突 预测，最终在齿状回中失去了突触终端。该模型还具有开发的属性 尽管没有 在这些神经元中表达人tau mRNA。这被解释为支持有一个想法 病理性tau的反式突触传播。我们已经将RTAUEC小鼠与App/PS1过表达者越过 在整个皮质中开发缠结的缠结模型和斑块，类似于人类 广告变化的许多早期病例的病理学。令人惊讶的是，斑块的添加似乎可以强烈加速 缠结的繁殖表型，也加剧了轴突营养不良，产生更严重的神经病变 在海马中。 tau过表达可以通过rtau ec小鼠中的多西环素来调节，模仿一些 抗TAU疗法的形式。因此，该模型将使我们能够剖析神经系统的详细时间过程 变性，测试假设关于定义的神经系统中tau淀粉样蛋白相互作用的假设，并检查 在疾病过程中各个点减少tau的后果。这些实验将有助于 提供有关广告最早阶段的病理学的见解，并突出了潜在的机会 疾病早期的治疗干预。