Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease

项目总结/摘要 阿尔茨海默病（AD）的病因、发病机制、进展及与病理的关系 临床表现，尚未完全了解。新的研究表明，炎症和小胶质细胞 激活是AD发病机制和进展的重要因素。tau蛋白与 小胶质细胞尤其重要，因为tau与AD最密切相关。传统上被接受的 这种相互作用的顺序是，促炎性的错误折叠的tau，引起小胶质细胞活化， 导致树突修剪并最终导致神经元细胞死亡。然而，最近出现的是， 活化本身可引起tau聚集和随后的传播。因此，这些因果关系 相互作用是有争议的，并且需要在人体内进行非常需要的阐明。这项提案的目的是 是了解tau蛋白，神经变性，小胶质细胞和 全身性炎症在人类AD的病因学和进展中的作用。该提案涉及一系列 原则性的统计和数学模型为基础的测试，将揭示这些关系，第一， 时间，直接在病人身上。该提案涉及一项新的前瞻性纵向研究， 使用新一代TSPO配体获得活化小胶质细胞的脑MRI和PET成像的患者 称为DPA-713和tau-PET成像，使用相对新颖的配体MK 6240。相同的成像协议 (MRI、DPA-713和MK 6240 PET）将在18个月和36个月随访时间点重复进行。所有受试者将 在基线时使用florbetaben PET测量淀粉样神经炎斑块密度。接下来，该提案涉及 通过数学模型开发和测试小胶质细胞炎症-tau相互作用的模型， 确定通过DPA-PET测量的局部小胶质细胞介导的神经炎症是否在AD中更高 频谱患者或认知正常的老年人;以及区域性小胶质细胞激活是否可预测 直接从tau蛋白和/或淀粉样蛋白。最后，这项拟议的研究包括测试tau的网络传播模型 和小胶质细胞。越来越多的动物数据暗示了tau蛋白通过大脑的跨神经元传递机制 网络.利用疾病传播的网络扩散模型，本建议将进一步研究 小胶质细胞在人类的tau蛋白直接进展。由于tau蛋白和小胶质细胞提供关于 随着病理学的发展，这项建议将决定是否结合影像学研究，测量两者 生物标志物将导致AD进展的独特的强大和预测性测试。鉴于快速发展的 了解小胶质细胞和全身炎症在痴呆症中的作用，目前的建议是及时的， 这是推进人类痴呆症研究的主题和必要条件。如果成功，它将给出第一个经过验证的 AD中病理和神经炎症之间因果相互作用的时空模型，催化 未来的进展，在消炎和有针对性的抗炎治疗。

Project Summary/Abstract The etiology, mechanism and progression of Alzheimer’s Disease (AD), and the relationship of AD pathology to clinical manifestations, are not fully understood. Emerging studies suggest that inflammation and microglial activation is an important contributor to AD pathogenesis and progression. The association between tau and microglia is especially critical, since tau is most closely associated with AD. The conventionally accepted sequence of this interaction is that misfolded tau, which is pro-inflammatory, causes microglial activation, leading to dendritic pruning and eventually neuronal cell death. However, it is recently emerging that microglial activation can itself cause tau aggregation and subsequent propagation. Therefore the causality of these interactions is controversial, and requires much needed elucidation in humans in vivo. The goal of this proposal is to understand the interaction and causal sequencing between tau, neurodegeneration, microglia and systemic inflammation in governing the etiology and progression of human AD. This proposal involves a series of principled statistical and mathematical model-based tests that will uncover these relationships, for the first time, directly in patients. This proposal involves a new prospective longitudinal study of 100 AD spectrum patients acquiring brain MRI and PET imaging of activated microglia using a new generation TSPO ligand called DPA-713 and tau-PET imaging using a relatively novel ligand, MK6240. The same imaging protocol (MRI, DPA-713 and MK6240 PET) will be repeated at 18- and 36-month follow up time points. All subjects will have amyloid neuritic plaque density measured at baseline using florbetaben PET. Next this proposal involves developing and testing a model of microglial inflammation-tau interaction via mathematical models to determine whether regional microglia-mediated neuroinflammation measured by DPA-PET is higher in AD spectrum patients or in cognitively normal older adults; and whether regional microglial activation is predictable directly from tau and/or amyloid. Finally, this proposed research includes testing a network spread model of tau and microglia. Mounting animal data implicate a trans-neuronal transmission mechanism of tau through brain networks. Using a network diffusion model of disease spread, this proposal will further investigate the role of microglia in tau progression directly in humans. Since tau and microglia provide complementary signal about evolving pathology, this proposal will determine whether combining imaging studies that measure both biomarkers will result in a uniquely powerful and predictive test of AD progression. Given the rapidly evolving understanding of the role of microglia and systemic inflammation in dementias, the current proposal is timely, topical and necessary for advancing human dementia research. If successful, it will give the first validated spatiotemporal model of the causal interactions between pathology and neuroinflammation in AD, catalyzing future advances in prognostication and targeted anti-inflammatory therapies.