Impact of TBI and Cognitive Decline on Alzheimer's Disease Brain-Derived Exosome Cargo

TBI 和认知能力下降对阿尔茨海默病脑源性外泌体货物的影响

• 批准号: 10662883
• 负责人: Victoria B Risbrough
• 金额: $ 194.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662883
• 关键词: Acute; Address; Age; Age-associated memory impairment; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Astrocytes; Attention; Award; Biological Assay; Biological Markers; Blood; Brain; Cells; Cerebrospinal Fluid; Chronic; Clinical Trials; Cognition; Cognitive; Complement; Cytoskeleton; Data; Diagnosis; Disease; Dizygotic Twins; Eligibility Determination; Endosomes; Genetic; Genotype; Heritability; Impaired cognition; Individual; Inflammatory; Injury; Liquid substance; Longitudinal cohort study; Magnetic Resonance Imaging; Membrane; Molecular; Monozygotic twins; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Injury; Neurons; Pathologic; Pathology; Pathway interactions; Peripheral; Phase; Plasma; Plasma Proteins; Post-Traumatic Stress Disorders; Proteins; Proteomics; Recording of previous events; Risk; Sampling; Surface; Synapses; Testing; Traumatic Brain Injury; Twin Multiple Birth; Twin Studies; Variant; Vesicle; Veterans; Vietnam; aged; apolipoprotein E-4; biobank; biomarker identification; biomarker performance; cell type; cognitive change; cohort; comorbidity; cytokine; exosome; experience; human old age (65+); mental function; middle age; neurogranin; neuroimaging; neuropathology; novel; persistent symptom; phenotypic data; specific biomarkers; tau Proteins; tau-1; tool; treatment trial; vesicular release

PROJECT SUMMARY ABSTRACT Exosomes remove proteins and cellular substituents, and also shuttle protein cargo between cells and also to the periphery. Unlike freely circulating proteins, exosomes are identified by surface markers that include designations of cell type origin. Astrocyte and neuronally-derived exosomes (ADEs and NDEs, respectively) from plasma are identified by specific membrane markers, providing an accessible substrate to identify biomarkers and mechanisms of neuropathology. The potential for NDEs to identify TBI-related biomarkers however is just beginning to be explored. Our lab has a large focus on exosome biomarkers in TBI and neurodegeneration. Our data demonstrate that Alzheimer's disease (AD) neuropathological proteins, amyloid-beta and phospho-tau are sequestered in NDEs and are more sensitive biomarkers of AD than free proteins in native plasma. In terms of Veterans with TBI, we and others have found that NDEs have increased levels of Aβ, proteins associated with neuronal injury and synaptic proteins. We have also shown that complement protein cargo in ADEs is also associated with AD. Although exciting, these studies represent relatively small studies in samples from younger individuals with limited information about the relationship between exosome protein cargo and functional changes. To examine CNS-enriched exosome proteins as biomarkers of TBI and associated cognitive decline in older individuals, we will leverage banked plasma samples from the Vietnam Era Twin Study of Aging (VETSA), a longitudinal cohort study of US Veterans who had a mean age of 56 at the first assessment wave and 67 at the most recently completed third assessment. In this Merit Award proposal we propose to determine the utility of neurodegenerative disease proteins within NDEs as biomarkers to predict cognitive change in aging twin Veterans with post-traumatic stress disorder and TBI and also to identify the mechanisms underlying the relationship between inflammatory pathways, cognition and neurodegeneration associated with TBI and PTSD in VETSA. Our overarching hypothesis is that remote TBI is associated with abnormalities in cytoskeletal and neuronal proteins in circulating NDEs. We also hypothesize that remote TBI causes chronic changes in central inflammatory tone which leads to abnormalities in complement and cytokine proteins in circulating ADEs

项目概要摘要 外泌体去除蛋白质和细胞取代基，还在细胞之间运送蛋白质货物，并将蛋白质运送到 外围。与自由循环的蛋白质不同，外泌体是通过表面标记来识别的，包括 细胞类型起源的名称。星形胶质细胞和神经源性外泌体（分别为 ADE 和 NDE） 通过特定的膜标记来识别血浆中的物质，从​​而提供可接近的底物来识别 神经病理学的生物标志物和机制。 NDE 识别 TBI 相关生物标志物的潜力 然而才刚刚开始探索。 我们的实验室主要关注 TBI 和神经退行性变中的外泌体生物标志物。我们的数据表明 阿尔茨海默病 (AD) 神经病理蛋白、β 淀粉样蛋白和磷酸 tau 蛋白被隔离在 NDE 和 NDE 是比天然血浆中的游离蛋白更敏感的 AD 生物标志物。就退伍军人而言 TBI，我们和其他人发现濒死体验中 Aβ 水平升高，Aβ 是与神经元损伤相关的蛋白质 和突触蛋白。我们还表明，ADE 中的补体蛋白货物也与 广告。尽管令人兴奋，但这些研究代表了针对年轻个体样本的相对较小的研究 关于外泌体蛋白货物和功能变化之间关系的信息有限。到 检查富含 CNS 的外泌体蛋白作为 TBI 的生物标志物以及老年人相关的认知能力下降 对于个人而言，我们将利用来自越南时代双胞胎衰老研究 (VETSA) 的血浆样本，该研究是一项 对美国退伍军人进行的纵向队列研究，他们在第一波评估时的平均年龄为 56 岁，在第二波评估时的平均年龄为 67 岁。 最近完成了第三次评估。在这个优异奖提案中，我们建议确定 濒死体验中的神经退行性疾病蛋白作为预测衰老双胞胎认知变化的生物标志物 患有创伤后应激障碍和 TBI 的退伍军人，并确定其背后的机制 与 TBI 和 PTSD 相关的炎症通路、认知和神经变性之间的关系 在 VETSA 中。我们的首要假设是，远程 TBI 与细胞骨架和细胞异常有关。 循环濒死体验中的神经元蛋白。我们还假设远程 TBI 会导致中枢神经系统的慢性变化。 炎症张力导致循环 ADE 中补体和细胞因子蛋白异常