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

了解阿尔茨海默病中 tau 蛋白病理学与小胶质细胞介导的炎症之间的动态相互作用

• 批准号: 10471976
• 负责人: Ajay Gupta
• 金额: $ 131.97万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471976
• 关键词: Address; Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Anti-Inflammatory Agents; Atrophic; Biological; Biological Markers; Biological Models; Brain; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Computer Models; Dementia; Diagnosis; Diagnostic; Diffusion; Disease; Disease Progression; Disease model; Education; Elderly; Etiology; Foundations; Functional disorder; Future; Generations; Genetic Risk; Glucose; Goals; Human; Image; Inflammation; Inflammatory; Investigation; Kinetics; Laboratories; Ligands; Linear Models; Longitudinal cohort; Longitudinal prospective study; Machine Learning; Magnetic Resonance Imaging; Measures; Mediating; Mediation; Microglia; Modeling; Modernization; Nerve Degeneration; Neurofibrillary Tangles; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Positron-Emission Tomography; Property; Protocols documentation; Public Health; Race; Research; Role; Science; Senile Plaques; Series; Serum; Signal Transduction; Specificity; Speed; Statistical Models; TREM2 gene; Testing; Time; Visit; animal data; base; brain magnetic resonance imaging; clinical application; clinical heterogeneity; density; disease phenotype; follow-up; imaging study; in vivo; inflammatory marker; insight; mathematical model; model design; neuroinflammation; neuron loss; novel; predictive modeling; predictive test; prognostication; sex; spatiotemporal; systemic inflammatory response; tau Proteins; tau aggregation; tau interaction; tau mutation; tractography; transmission process

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.

项目概要/摘要 阿尔茨海默病（AD）的病因、机制和进展以及AD病理学的关系 就临床表现而言，尚不完全清楚。新兴研究表明炎症与小胶质细胞有关。 tau 蛋白激活是 AD 发病机制和进展的重要因素。 小胶质细胞尤其重要，因为 tau 蛋白与 AD 关系最为密切。 这种相互作用的顺序是，错误折叠的 tau 蛋白具有促炎作用，会导致小胶质细胞激活， 导致树突修剪并最终导致神经元细胞死亡。然而，最近出现了小胶质细胞。 激活本身可以引起 tau 聚集和随后的传播，因此它们之间存在因果关系。 相互作用是有争议的，需要在人体体内进行非常必要的阐明。该提案的目标是。 是为了了解 tau、神经退行性变、小胶质细胞和 系统性炎症控制人类 AD 的病因和进展 该提案涉及一系列内容。 基于统计和数学模型的原理测试将首次揭示这些关系 该提案涉及对 100 个 AD 谱进行新的前瞻性纵向研究。 患者使用新一代 TSPO 配体获得激活小胶质细胞的脑部 MRI 和 PET 成像 称为 DPA-713 和使用相对新颖的配体 MK6240 的 tau-PET 成像相同的成像方案。 （MRI、DPA-713 和 MK6240 PET）将在 18 个月和 36 个月的随访时间点重复进行。 使用 florbetaben PET 在基线测量淀粉样神经炎斑块密度。 通过数学模型开发和测试小胶质细胞炎症-tau 相互作用模型 确定通过 DPA-PET 测量的区域小胶质细胞介导的神经炎症在 AD 中是否较高 谱系患者或认知正常的老年人；区域小胶质细胞的激活是否是可预测的 最后，这项拟议的研究包括测试 tau 的网络传播模型。 动物数据表明 tau 蛋白通过大脑进行跨神经元传递机制。 该提案将利用疾病传播的网络扩散模型进一步研究网络的作用。 小胶质细胞直接参与人类的 tau 进展，因为 tau 和小胶质细胞提供了关于 tau 的互补信号。 不断发展的病理学，该提案将确定是否将测量两者的影像学研究结合起来 鉴于 AD 进展的迅速发展，生物标志物将为 AD 进展提供独特而强大的预测性测试。 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， 如果成功，它将成为第一个经过验证的研究。 AD 病理与神经炎症之间因果相互作用的时空模型，催化 预测和靶向抗炎治疗的未来进展。