The Role of the Tau in Homeostatic Scaling and Mechanisms of Alzheimer's Disease

项目摘要 对神经网络活动的调节机制知之甚少。 微管相关蛋白tau是阿尔茨海默病(AD)的关键致病蛋白。长期目标 是作为一名神经病理学家和一名分子神经学家发展独立的职业生涯 从人类神经病理学观察到分子理解以获得对AD的新见解 发病机制及治疗策略。这项研究最初集中在tau如何调节神经元。 以及这一调控与AD发病机制的关系。初步研究表明tau本地化是 受动态平衡调节，突触可塑性的一种关键形式与AD有关。总体目标 本应用的目的是(I)阐明tau在动态平衡调节中的作用，(Ii)定义 在动态平衡调节过程中tau的分子相互作用，以及(Iii)决定动态平衡调节在 培养的AD模型突触后tau和AMPA受体的变化。这一点的中心假设是 建议是动态平衡的伸缩通路由tau调节，并由Aβ利用来创建后 阿尔茨海默病的突触改变。这一假说将使用tau和ampa的实时神经元荧光成像进行验证。 受体，抑制或击倒tau和对体内平衡调节至关重要的蛋白质，以及质谱学 稳态缩放条件下tau相互作用蛋白的分析。这个项目的基本原理是 对tau功能及其与阿尔茨海默病发病机制关系的深入了解可能会带来新的 研究AD疗法的途径，同时提供机会建立候选人的 作为一名分子神经学家的独立性。这一努力将直接涉及理查德博士的指导 胡加尼尔是突触可塑性分子机制领域的专家神经学家，他将 约翰霍普金斯大学阿尔茨海默病研究的丰富和协作环境的优势 大学。这项工作将建立在候选人在神经退行性疾病病理学方面的坚实基础上 以及研究，将由突触生物学、成像技术、人类诱导的 多能干细胞(IPSCs)和生物统计分析，这些领域对拟议的工作和未来至关重要 调查。拟议的研究具有创新性，因为它定义了tau的新角色和相互作用 由神经元活动调节，并直接测试动态平衡调节对AD相关的贡献 突触的变化。这项拟议的研究意义重大，因为它将为新的生物学提供洞察力 Tau的功能和相互作用及其与AD发病机制的关系。归根结底，了解这些 机制可能阐明tau在散发性AD中的作用，并导致新的治疗策略。

Project Summary Little is unknown about the mechanisms involved in the regulation of neuronal network activity by the microtubule associated protein tau, a key pathogenic protein in Alzheimer's disease (AD). The long term goal is to develop an independent career as a neuropathologist and a molecular neuroscientist integrating observations from human neuropathology with molecular understanding to gain new insights into AD pathogenesis and therapeutic strategies. This research is initially focused on how tau regulates neuronal activity and how this regulation relates to mechanisms of AD. Preliminary studies show tau localization is regulated by homeostatic scaling, a critical form of synaptic plasticity implicated in AD. The overall objectives for this application are to (i) elucidate the role of tau in homeostatic scaling, (ii) define alterations in the molecular interactions of tau during homeostatic scaling, and (iii) determine the role of homeostatic scaling in the post-synaptic alterations of tau and AMPA receptors in culture models of AD. The central hypothesis of this proposal is that homeostatic scaling pathways are regulated by tau and are utilized by Aβ to create post- synaptic changes in AD. This hypothesis will be tested using live neuron fluorescent imaging of tau and AMPA receptors, inhibition or knock-down of tau and proteins critical to homeostatic scaling, and mass spectrometry analysis of tau interacting proteins under homeostatic scaling conditions. The rationale for this project is that improved understanding of tau functions and their relationship to the pathogenesis of AD may lead to new avenues of investigation for AD therapies while offering an opportunity to establish the candidate's independence as a molecular neuroscientist. This effort will directly involve the mentorship of Dr. Richard Huganir, an expert neuroscientist in the field of molecular mechanisms synaptic plasticity, and will take advantage of the rich and collaborative environment of Alzheimer's disease research at Johns Hopkins University. This work will build on the candidate's strong foundation in neurodegenerative disease pathology and research, which will be supplemented by training in synaptic biology, imaging techniques, human induced pluripotent stem cells (iPSCs), and biostatistical analysis, areas critical to the proposed work and to future investigations. The proposed research is innovative because it defines novel roles and interactions of tau regulated by neuronal activity, and it directly tests the contribution of homeostatic scaling to AD-related synaptic changes. The proposed research is significant because it will provide insight into novel biologic functions and interactions of tau, and their relationship to AD pathogenesis. Ultimately, knowledge of these mechanisms may elucidate of the contribution of tau to sporadic AD and lead to novel therapeutic strategies.