Exosome biology in Alzheimer's disease and concussion

阿尔茨海默病和脑震荡中的外泌体生物学

• 批准号: 10468223
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 60万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468223
• 关键词: 3xTg-AD mouse; Acute; Adult; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Assessment tool; Astrocytes; Biological; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; Brain Concussion; Brain Injuries; Brain Pathology; Cells; Clinical; Cognitive; Cognitive deficits; Cohort Studies; Data; Dementia; Diagnostic; Disease; Drug Targeting; Elderly; Equilibrium; Exposure to; Female; Future; Genetic; Genetic Diseases; Goals; Grant; Health; Human; Human Resources; Ice Hockey; Impaired cognition; In Vitro; Inflammation; Injections; Injury; Italy; Label; Lacrosse; Lead; Longitudinal Studies; Manufactured football; Measurement; Mental Depression; Military Personnel; Molecular; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Newborn Infant; Pathologic; Pathology; Preventive treatment; Research; Research Personnel; Risk; Seeds; Sports; Stream; Surface; Technology; Testing; Text; Transgenes; Transgenic Mice; Trauma; Wild Type Mouse; age related; aged; amyloid pathology; base; biomarker panel; brain health; cohort; dementia risk; design; diagnostic tool; disability; drug development; epidemiology study; equilibration disorder; exosome; experimental study; extracellular vesicles; in vivo; male; mild traumatic brain injury; military service; mouse model; nanosized; neuropathology; normal aging; novel; novel marker; primary outcome; prion-like; prognostic; programs; pup; response; secondary outcome; tau Proteins; tau aggregation; uptake

ABSTRACT Repeated concussions (mild Traumatic Brain Injury, mTBI), which are particularly prevalent in athletes and military personnel, can lead to long-term brain health issues including dementia, depression, and other psychiatric conditions. Recent studies suggest that mTBIs may give rise to increased risk for Alzheimer's disease (AD) or other AD-related dementias (ADRDs), but there are few conclusive studies, and no reliable blood biomarkers available as a predictive diagnostic tool. We are studying a unique cohort of NCAA Division I athletes in high impact sports to develop a reliable blood biomarker assessment and examine biological mechanisms for AD/ADRD risk after multiple mTBIs. To our knowledge, studies have not been conducted using neuron- or astrocyte-derived exosomes (NDEs vs. ADEs) to detect Tau and amyloid pathology and seeding capacity from those with sports-related brain injuries. The revised application now contains more specifics regarding the existing cohort and the experiments proposed. The overall hypothesis of this project is that exosome alterations after repeated mTBIs reflect and contribute to long-term risk for AD/ADRD. In Aim 1, we will test the hypothesis that NDE and ADE biomarkers correlate with cognitive dysfunction following one or repeated mTBIs in humans. Experiments in this Aim will validate exosomal biomarkers and distinguish between cargos obtained from NDEs vs. ADEs. In Aim 2, we will test the hypothesis that age-dependent and genetics-driven cognitive decline and brain pathology are accelerated following either repeated mTBIs or injection of TBI-derived exosomes in mice. The relationship between a transgene leading to amyloid and Tau aggregation and added trauma via repeated mTBIs will be examined. In Aim 3, we hypothesize that NDEs vs. ADEs from athletes with multiple mTBIs can elicit differential responses in primary cortical neuronal cultures. We propose that NDEs and/or ADEs from athletes with repeated mTBIs can propagate AD pathology to primary neuronal cultures. Our interdisciplinary team has the unique potential to reveal molecular mechanisms involved in AD pathology after mTBIs, using a unique cohort consisting of male and female Division I athletes including baseline and post- concussion measurements. In the revised submission, we are proposing to use primary cultures from 3xTg-AD or wildtype mouse pups, to connect the in vivo studies in Aim 2 with the in vitro studies in Aim 3. The major goal of this research program is to develop sensitive biomarkers post-concussion that could predict future risk for AD/ADRD and to reveal mechanisms for exosome propagation of brain pathology post-mTBI. The unique value of this program is the interdisciplinary team, including both mouse models and human studies, the large cohort of Division I athletes, and the long-term biomarker studies proposed. Based on the biological mechanisms examined herein, and the wealth of preliminary data, we will be able to design better preventative treatment options long-term for those with one or several mTBIs who are at risk of developing dementia.

抽象的 反复脑震荡（轻度脑损伤，mTBI），在运动员和 军事人员可以导致长期的大脑健康问题，包括痴呆症，抑郁症和其他 精神病。最近的研究表明，MTBI可能导致阿尔茨海默氏病的风险增加 （AD）或其他与广告相关的痴呆症（ADRDS），但很少有结论性研究，没有可靠的血液 可作为预测诊断工具可用生物标志物。我们正在研究NCAA分区I运动员的独特队列 在高影响力运动中，以开发可靠的血液生物标志物评估并检查生物学机制 多个mtbis之后的AD/ADRD风险。据我们所知，尚未使用神经元或 星形胶质细胞衍生的外泌体（NDES与ADES）可检测TAU和淀粉样病理学和播种能力 患有运动有关的脑部受伤的人。修订的应用程序现在包含有关 现有的队列和提出的实验。该项目的总体假设是外泌体 重复MTBI后的改变反映并导致AD/ADRD的长期风险。在AIM 1中，我们将 检验NDE和ADE生物标志物与认知功能障碍相关的假设，或重复一次 人类中的mtbis。此目标中的实验将验证外泌体生物标志物并区分碳 从NDES与ADES获得。在AIM 2中，我们将检验以下假设，即依赖年龄和遗传学驱动的假设 重复MTBI或注射TBI衍生后，认知能力下降和脑部病理会加速 小鼠的外泌体。转基因导致淀粉样蛋白和tau聚集的关系，并添加 将检查重复MTBI的创伤。在AIM 3中，我们假设NDES与运动员的ADS 多个MTBI可以在原发性皮质神经元培养物中引起差异反应。我们建议NDE 和/或反复MTBI的运动员的AD可以将AD病理传播到原发性神经元培养物中。 我们的跨学科团队具有揭示AD病理涉及的分子机制的独特潜力 MTBIS之后，使用由男性和女性I分区运动员组成的独特队列，包括基线和后 脑震荡测量。在修订的提交中，我们建议使用3xtg-ad的原始文化 或野生型小鼠幼崽，将AIM 2中的体内研究与AIM 3的体外研究联系起来。 该研究计划的目标是在脑后发展敏感的生物标志物，以预测未来的风险 用于AD/ADRD并揭示MTBI后脑病理外泌体传播的机制。独特 该计划的价值是跨学科团队，包括鼠标模型和人类研究，大型 I分区运动员队列以及长期生物标志物研究提出了。基于生物学 本文检查的机制以及初步数据的财富，我们将能够设计更好的预防措施 对于有一个或几个MTBI的患者，患有痴呆症风险的人长期治疗。