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。我们正在研究一支独特的I组运动员队伍，在高影响力的运动中开发可靠的 多次MTBI后，血液生物标记物评估和检查AD/ADRD风险的生物学机制。 此外，我们正在使用新的外体生物标记技术来确定Tau和淀粉样蛋白的种子和 聚集能力，以及使用AD动物模型的多个MTBI的影响。据我们所知， 尚未使用神经元或星形胶质细胞来源的外切体(NDE与ADE)来检测Tau 以及运动相关脑损伤患者的淀粉样蛋白病理和种子能力。整体而言 该项目的假设是，重复MTBI后的外体改变反映并促进了长时间的- AD/ADRD的期限风险。为了解决这一假设，我们制定了三个具体目标。在目标1中，我们将 检验NDE和ADE生物标记物与以下平衡和/或认知障碍相关的假设 人类的一次或多次MTBI。在目标2中，我们将检验这样的假设，即重复MTBI或注射TBI- 衍生的外切体加速了与衰老和阿尔茨海默病相关的小鼠认知功能障碍和脑病理。 在目标3中，我们在体外检测暴露于NDE或ADE的细胞是否显示出来自患有多发性MTBI的运动员的细胞 改变外切体的生物发生、释放或摄取机制，重点关注内源性外切体是如何 培养的神经元和神经胶质细胞在暴露于运动员的外源外体后形成和释放 或者没有MTBIS。 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。这些跨学科的研究还可以区分 个体的基因型别(如3xTg-AD小鼠)与外界因素(MTBI)对AD相关病理的影响。少校 这项研究计划的目标是开发更敏感的脑震荡后生物标记物，可以预测未来 AD/ADRD的风险，并揭示mTBI后外显体改变的机制。它的独特价值在于 该计划是跨学科团队，包括老鼠模型和人体研究，这是 我司运动员的长期生物标记物研究建议。基于生物学机制 在这里检查，以及丰富的初步数据，我们将能够设计出更好的预防性治疗 长期适用于那些患有一种或多种MTBI的人，他们有患痴呆症的风险。

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. We are studying a unique cohort of 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. Further, we are using novel exosome biomarker technology to determine Tau and amyloid seeding and aggregation capacity, as well as the impact of multiple mTBIs using an animal model for AD. 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 overall hypothesis of this project is that exosome alterations after repeated mTBIs reflect and contribute to long- term risk for AD/ADRD. To address this hypothesis, we have developed three specific Aims. In Aim 1, we will test the hypothesis that NDE and ADE biomarkers correlate with balance and/or cognitive impairment following one or repeated mTBIs in humans. In Aim 2, we will test the hypothesis that repeated mTBIs or injection of TBI- derived exosomes accelerates cognitive dysfunction and brain pathology associated with aging and AD in mice. In Aim 3 we examine in vitro whether cells exposed to NDEs or ADEs from athletes with multiple mTBIs exhibit altered exosome biogenesis, release or uptake mechanisms with a focus on how endogenous exosomes are formed and released from cultured neurons and glia after exposure to exogenous exosomes from athletes with or without mTBIs. 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. These interdisciplinary studies can also distinguish between long-term effects of an individual's genotype (e.g., 3xTg-AD mice) vs. external factors (mTBIs) on AD-related pathology. The major goal of this research program is to develop more sensitive biomarkers post-concussion that could predict future risk for AD/ADRD and to reveal mechanisms for exosome alterations 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, as well as 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.