Pathological and Functional Impact of Tauopathy in vivo

神经退行性病变是许多神经退行性疾病的共同特征，其中最常见的是阿尔茨海默病（AD）。虽然在导致缠结形成的致病途径中有几种蛋白质被破坏，但微管结合蛋白tau是重要的关注点，因为它是AD脑中缠结的主要组分，并且tau的突变可引起神经退行性疾病，如额叶颞叶痴呆。了解tau如何成为致病性的，以及致病性tau如何破坏细胞的正常功能。 最终导致其死亡的神经元是该计划的总体目标。为了解决这些问题，我们采取了多学科方法。项目1将检查在不同阶段有和没有神经病理学的单个神经元的基因谱，以确定在疾病过程中哪些通路受到影响。项目2将研究tau的周转和运输。项目3将使用体内成像研究tau蛋白病对神经元完整性的影响，项目4将通过研究致病性tau蛋白形成如何影响系统完整性，进一步将这些观察结果纳入功能背景。项目5将检查磷酸化或聚集对致病过程的贡献，并将测试 靶向这些系统，以及探索Abeta在缠结形成中的作用，以及使用Abeta靶向剂来减少AD的淀粉样蛋白和缠结病理。该计划将主要使用一种新的小鼠模型，即hTau系，其具有与AD密切相关的进行性tau蛋白病。将通过使用鼠标husbandy核心来促进该模型向计划参与者的分发，并通过使用行政核心来促进咨询小组的工作和反馈的协调。项目参与者的个人项目和集体专业知识将协同产生一个良好的控制丰富的信息，关于如何，为什么致病性tau蛋白的形成，以及功能的影响， 在疾病进展的不同阶段的tau蛋白病。这些信息，加上明智地使用相关的概念验证治疗候选药物，也将开始解决如何最好地开始治疗tau蛋白病如AD的问题。

Neurofibrillary pathology is a common feature of a large number of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Although several proteins are disrupted in the pathogenic pathway leading to tangle formation, the microtubule binding protein tau is of significant interest as it is a major component of tangles in the AD brain, and mutations in tau can cause neurodegenerative diseases such as frontal temporal lobe dementia. Understanding how tau becomes pathogenic, and how pathogenic tau disrupts the normal functioning of the neuron ultimately leading to its death are the overall goals of this program. To address these questions, we have taken a multidisciplinary approach. Project 1 will examine gene profiles in single neurons with and without neurofibrillary pathology at different stages to identify what pathways are affected during the disease process. Project 2 will look at the turnover and transport of tau. Project 3 will look at the effect of tauopathy on neuronal integrity using in vivo imaging and project 4 will further put these observations into functional context by examining how pathogenic tau formation impacts system integrity. Project 5 will examine the contribution of phosphorylation or aggregation to the pathogenic process, and will test therapeutic agents that target these systems, as well as explore the role of Abeta in tangle formation, and the use of an Abeta targeting agent to reduce both the amyloid and tangle pathologies of AD. The program will mainly use a new mouse model, the hTau line, that has progressive tauopathy of great relevance to AD. The distribution of this model to program participants will be facilitated by the use of a mouse husbandy core, and coordination of effort and feedback from advisory groups will be facilitated by the use of an administrative core. The individual projects and collective expertise of the program participants will synergize to generate a well-controlled wealth of information about how, and why pathogenic tau forms, and the functional impact of tauopathy at different stages of disease progression. This information, coupled with the judicious use of relevant proof-of concept therapeutic candidates will also begin to address issues of how best to start treating tauopathies such as AD.