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: 10577115
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 61.38万
• 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/10577115
• 关键词: Exosome; biology; Alzheimer; disease; concussion

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.

摘要 反复脑震荡（轻度创伤性脑损伤，mTBI），这在运动员中特别普遍， 军事人员，可导致长期的大脑健康问题，包括痴呆症，抑郁症，和其他 精神状况最近的研究表明，mTBI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。我们正在研究一个独特的队列，一级运动员在高冲击运动，以制定一个可靠的 血液生物标志物评估和检查多次mTBI后AD/ADRD风险的生物学机制。 此外，我们正在使用新的外泌体生物标志物技术来确定Tau和淀粉样蛋白的接种， 聚集能力，以及使用AD动物模型的多种mTBI的影响。据我们所知， 尚未进行使用神经元或星形胶质细胞衍生的外泌体（NDEs vs. ADEs）检测Tau的研究 以及淀粉样蛋白病理学和播种能力。整体 该项目的假设是，重复mTBI后的外泌体改变反映并有助于长期- AD/ADRD的长期风险。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 测试NDE和ADE生物标志物与以下平衡和/或认知障碍相关的假设： 在人类中发生一次或多次mTBI。在目标2中，我们将检验重复mTBI或注射TBI的假设- 衍生的外泌体加速小鼠中与衰老和AD相关的认知功能障碍和脑病理学。 在目标3中，我们在体外研究了暴露于来自患有多种mTBI的运动员的NDE或ADE的细胞是否表现出 改变外泌体生物发生、释放或摄取机制，重点关注内源性外泌体是如何 在暴露于来自运动员的外源性外泌体后， 或没有mTBI。 我们的跨学科团队具有独特的潜力，以揭示参与AD病理学的分子机制 mTBI后，使用由男性和女性一级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也可以区分长期影响的一个 个体的基因型（例如，3xTg-AD小鼠）与外部因素（mTBI）对AD相关病理学的影响。主要 这项研究计划的目标是开发出更敏感的脑震荡后生物标志物， AD/ADRD的风险，并揭示mTBI后外泌体改变的机制。这个独特的价值 计划是跨学科的团队，包括小鼠模型和人类研究，大型队列研究， 我司运动员，并提出了长期的生物标志物研究。根据生物学机制 通过本文的研究，以及大量的初步数据，我们将能够设计出更好的预防性治疗方法。 对于那些有一个或几个mTBI谁是在发展痴呆症的风险长期选择。