Exosome biology in Alzheimer's disease and concussion

摘要 反复脑震荡(轻度创伤性脑损伤，mTBI)，在运动员和 军事人员，会导致长期的大脑健康问题，包括痴呆症、抑郁症和其他 精神疾病。最近的研究表明，MTBIs可能会增加患阿尔茨海默病的风险 (AD)或其他AD相关痴呆(ADRD)，但很少有结论性研究，也没有可靠的血液 生物标志物可作为预测性诊断工具。我们正在研究一群独特的NCAA I组运动员 在高冲击性运动中开发可靠的血液生物标记物评估和研究生物机制 多个MTBI后的AD/ADRD风险。据我们所知，还没有使用神经元-或 星形胶质细胞来源的外切体(NDE与ADE)用于检测牛磺酸和淀粉样蛋白的病理和播种能力 那些有运动相关脑损伤的人。修订后的应用程序现在包含有关 现有的队列和提出的实验。这个项目的总体假设是外显体 反复MTBI后的改变反映并导致AD/ADRD的长期风险。在目标1中，我们将 检验NDE和ADE生物标记物与认知功能障碍相关的假设 人类的MTBIS。这一目标的实验将验证外体生物标记物并区分货物 从NDE与ADE中获得。在目标2中，我们将检验年龄依赖和遗传驱动的假设 重复MTBI或注射脑损伤衍生的脑损伤可加速认知功能减退和脑病理 小鼠体内的外切体。导致淀粉样蛋白的转基因与Tau聚集和Add的关系 将对重复的MTBI造成的创伤进行检查。在目标3中，我们假设来自运动员的NDE与ADE 多个MTBI可以在原代皮质神经元培养中引起不同的反应。我们建议NDES 和/或反复发生MTBI的运动员的ADE可以将AD病理传播到原代神经元培养。 我们的跨学科团队有独特的潜力来揭示AD病理中涉及的分子机制 在MTBIS之后，使用由I组男运动员和女运动员组成的独特队列，包括基线和后 脑震荡测量。在修订的意见书中，我们提议使用公元3xTg-AD的原代培养物 或野生型小鼠，将AIM 2的体内研究与AIM 3的体外研究联系起来。 这项研究计划的目标是开发脑震荡后可以预测未来风险的敏感生物标记物。 研究AD/ADRD的发病机制，揭示脑损伤后病理变化的外切体传播机制。独一无二的 这个项目的价值在于跨学科团队，包括小鼠模型和人体研究，大型 I组运动员队列，并建议进行长期生物标志物研究。基于生物学的 在这里研究的机制，以及丰富的初步数据，我们将能够设计出更好的预防措施 对于那些有患痴呆症风险的一种或多种MTBI的人来说，治疗方案是长期的。

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.