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

项目摘要 外泌体去除蛋白质和细胞取代物，并且还在细胞之间穿梭蛋白质货物，并且还将蛋白质转运至细胞。 外围。与自由循环的蛋白质不同，外泌体由表面标记物识别，包括 细胞类型来源的名称。星形胶质细胞和神经源性外泌体（分别为ADE和NDE） 通过特定的膜标记物识别，提供了一种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，这只是刚刚开始探索。 我们的实验室主要关注TBI和神经变性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淀粉样蛋白和磷酸化tau蛋白被隔离在 与天然血浆中的游离蛋白相比，NDE和是更敏感的AD生物标志物。在退伍军人方面， TBI，我们和其他人发现NDE增加了Aβ水平，A β是与神经元损伤相关的蛋白质 和突触蛋白。我们还发现，ADE中的补体蛋白货物也与 AD.虽然令人兴奋，但这些研究代表了对年轻个体样本的相对较小的研究 关于外泌体蛋白质货物和功能变化之间的关系的信息有限。到 研究CNS富集的外泌体蛋白作为TBI和老年人相关认知下降的生物标志物 我们将利用越南时代衰老双胞胎研究（VETSA）的库存血浆样本， 美国退伍军人的纵向队列研究，第一次评估波时平均年龄为56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 NDE中神经退行性疾病蛋白作为生物标志物预测老年双胞胎的认知变化 退伍军人与创伤后应激障碍和创伤性脑损伤，并确定潜在的机制， TBI和PTSD相关的炎症通路、认知和神经退行性变之间的关系 在VETSA。我们的总体假设是，远程TBI与细胞骨架异常有关， 神经元蛋白在循环NDEs。我们还假设远程TBI会导致中枢神经系统的慢性变化 导致循环ADE中补体和细胞因子蛋白异常的炎性紧张