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: 10317655
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: --
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 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 2021-10-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317655
• 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; 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; tool; 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（轻度创伤性脑损伤，mTBI），在运动员和 军事人员可能会导致长期的大脑健康问题，包括痴呆、抑郁症和其他 精神状况。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），但确凿的研究很少，也没有可靠的血液 生物标志物可用作预测诊断工具。我们正在研究一群独特的 NCAA I 级运动员 在高强度运动中开发可靠的血液生物标志物评估并检查生物机制 多次 mTBI 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（NDE 与 ADE）用于检测 Tau 和淀粉样蛋白病理学以及接种能力 患有与运动相关的脑损伤的人。修订后的申请现在包含有关 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 mTBIs 后的变化反映并导致 AD/ADRD 的长期风险。在目标 1 中，我们将 检验 NDE 和 ADE 生物标志物与一次或重复的认知功能障碍相关的假设 人类 mTBIs。该目标的实验将验证外泌体生物标志物并区分货物 从 NDE 与 ADE 获得。在目标 2 中，我们将检验年龄依赖性和遗传驱动的假设 重复 mTBI 或注射 TBI 衍生药物后，认知能力下降和脑部病理学会加速 小鼠的外泌体。导致淀粉样蛋白和 Tau 聚集的转基因之间的关系并添加 将检查重复 mTBIs 造成的创伤。在目标 3 中，我们假设患有以下疾病的运动员的 NDE 与 ADE 多个 mTBI 可以在原代皮质神经元培养物中引起不同的反应。我们建议濒死体验 和/或患有反复 mTBI 的运动员的 ADE 可以将 AD 病理传播到原代神经元培养物中。 我们的跨学科团队具有揭示 AD 病理学分子机制的独特潜力 在 mTBIs 后，使用由男性和女性 I 级运动员组成的独特队列，包括基线和后期 震荡测量。在修订后的提交中，我们建议使用来自 3xTg-AD 的原代培养物 或野生型小鼠幼崽，将目标 2 中的体内研究与目标 3 中的体外研究联系起来。 该研究计划的目标是开发脑震荡后敏感的生物标志物，可以预测未来的风险 用于 AD/ADRD 并揭示 mTBI 后脑病理学外泌体传播的机制。独特的 该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 级运动员队列，以及提出的长期生物标志物研究。基于生物学 根据本文研究的机制以及丰富的初步数据，我们将能够设计更好的预防措施 为患有一种或多种 mTBI 且有患痴呆症风险的患者提供长期治疗选择。