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.

摘要