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: 10614055
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 60万
• 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/10614055
• 关键词: 3xTg-AD mouse; AD transgenic mice; Acceleration; 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 specimen; Brain; Brain Concussion; Brain Injuries; Brain Pathology; Cells; Central Nervous System; Clinical; Cognitive; Cognitive deficits; Cohort Studies; Data; Dementia; Diagnostic; Disease; Drug Targeting; Elderly; Equilibrium; Exposure to; Female; Future; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Goals; Grant; Health; Human; Human Resources; Ice Hockey; Impaired cognition; In Vitro; Inflammation; Injections; Injury; Label; Lacrosse; Lead; Longitudinal Studies; Manufactured football; Measurement; Mental Depression; Military Personnel; Molecular; Mus; Neurodegenerative Disorders; Neurons; Newborn Infant; Pathologic; Pathology; Preventive treatment; Research; Research Personnel; Risk; Sports; Stream; Surface; Technology; Testing; Text; Transgenes; Trauma; Wild Type Mouse; age related; aged; amyloid pathology; biomarker panel; blood-brain barrier crossing; brain health; cell cortex; cohort; dementia risk; design; diagnostic tool; 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; 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

项目成果

Biomarkers show value of studying dementia in Down syndrome.

生物标志物显示了研究唐氏综合症痴呆的价值。

• DOI: 10.1038/s41582-021-00558-w
• 发表时间: 2021
• 期刊: Nature reviews. Neurology
• 作者: Granholm,Ann-Charlotte;Ledreux,Aurélie
• 通讯作者: Ledreux,Aurélie

Extracellular vesicles from the CNS play pivotal roles in neuroprotection and neurodegeneration: lessons from in vitro experiments.

来自中枢神经系统的细胞外囊泡在神经保护和神经变性中发挥着关键作用：体外实验的教训。

• DOI: 10.20517/evcna.2023.07
• 发表时间: 2023
• 期刊: Extracellular vesicles and circulating nucleic acids
• 作者: Colvett,Isaac;Saternos,Hannah;Coughlan,Christina;Vielle,Anne;Ledreux,Aurélie
• 通讯作者: Ledreux,Aurélie

A Cohort Study of the Temporal Stability of ImPACT Scores Among NCAA Division I Collegiate Athletes: Clinical Implications of Test-Retest Reliability for Enhancing Student Athlete Safety.

NCAA I 级大学运动员 ImPACT 分数时间稳定性的队列研究：重测可靠性对增强学生运动员安全的临床意义。

• DOI: 10.1093/arclin/acaa047
• 发表时间: 2020
• 期刊: Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists
• 作者: Mason,SaraJ;Davidson,BradleyS;Lehto,Marybeth;Ledreux,Aurélie;Granholm,Ann-Charlotte;Gorgens,KimA
• 通讯作者: Gorgens,KimA

Long-Term Effects of SARS-CoV-2 in the Brain: Clinical Consequences and Molecular Mechanisms.

• DOI: 10.3390/jcm12093190
• 发表时间: 2023-04-28
• 期刊: JOURNAL OF CLINICAL MEDICINE
• 影响因子: 3.9
• 作者: Granholm, Ann-Charlotte