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: 10317631
• 负责人: Ajay Gupta
• 金额: $ 114.16万
• 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/10317631
• 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; Structure; TREM2 gene; Testing; Time; Visit; animal data; base; 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; prognostic; 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.

项目总结/文摘