Effects of mild traumatic brain injury in a mouse model of cerebral amyloid angiopathy

轻度创伤性脑损伤对脑淀粉样血管病小鼠模型的影响

• 批准号: 10648555
• 负责人: Lisa Suzanne Robison
• 金额: $ 15.4万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648555
• 关键词: Acute; Adolescence; Affect; Age; Age Months; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Athletic; Behavior; Behavioral; Blood Vessels; Boxing; Brain; Brain Injuries; Brain hemorrhage; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Cognitive; Cognitive deficits; Dementia; Diffuse Axonal Injury; Domestic abuse; Elderly; Experimental Designs; Goals; Head; Hockey; Impaired cognition; Impairment; Individual; Injury; Intervention; Ischemic Stroke; Learning; Link; Literature; Manufactured football; Memory; Modeling; Mus; Nerve Degeneration; Neuronal Plasticity; Outcome; Pathologic; Pathology; Persons; Procedures; Proteins; Protocols documentation; Recording of previous events; Risk; Soccer; Stroke; Synapses; Tauopathies; Time; Transgenic Mice; Traumatic Brain Injury; Unconscious State; Work; amyloid pathology; anxiety-like behavior; biological sex; chronic traumatic encephalopathy; contact sports; dementia risk; interest; intimate partner violence; memory recognition; mild traumatic brain injury; military service; mouse model; neuroinflammation; neuropathology; novel; object recognition; prevent; stroke risk; tau-1; time interval; vascular cognitive impairment and dementia; white matter damage; young adult

Traumatic brain injury (TBI) is a condition in which normal brain function is impaired by an external force. TBI is estimated to affect ~69 million people worldwide each year. Mild TBI’s are the most common form of brain injury (~70-90% of all cases), characterized by little-to-no time unconscious and minimal observable deficits immediately post-injury. Mild brain injuries are commonly attributed to participation in contact sports (e.g. boxing, football, soccer, hockey), military service, and as a result of intimate partner violence. Even mild TBI, especially following repeated injuries, has devastating acute and long-term consequences, including an increased risk of stroke and dementia. Given the clear evidence that TBI increases the risk of dementia in later life, it is of great interest to determine the mechanisms that drive the relationship between different types of TBIs and various dementia-associated neuropathologies, so that targets for intervention may be identified. Repetitive mild TBI has been most notably associated with chronic traumatic encephalopathy (a tauopathy), though some evidence suggests it may also contribute to Alzheimer’s and other neurodegenerative conditions. However, less is known about whether cerebral amyloid angiopathy (CAA) may also be a mechanism linking TBI to dementia. CAA is the accumulation of amyloid protein (most commonly beta-amyloid, associated with Alzheimer's disease) within the cerebral vasculature, contributing to increased risk of dementia [both vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease], as well as ischemic and hemorrhagic stroke. Increased levels of CAA are observed in former athletes, who tend to have a history of repetitive mild brain injuries. Experimental designs using animal models are needed to determine whether and how repetitive mild TBI influences the initiation and progression of CAA and related pathology. Here, we will subject Tg-SwDI mice (a transgenic mouse model of CAA) to repetitive mild TBI (1x/day for 5 consecutive days) starting at ~2 months of age. This age is roughly equivalent to late adolescence/young adulthood, when TBI is most common, and is prior to the onset of significant CAA pathology and cognitive impairment in this strain. We will then determine whether cognitive-behavioral deficits and neuropathology are altered at two time-points post-TBI (short-term: 7 days and longer-term: 3 months). Additionally, we will investigate whether biological sex moderates the relationship between repetitive mild TBI and CAA-associated outcomes. Our long-term goal is to identify mechanisms linking TBI and increased dementia risk, which may in turn reveal novel targets for treatment.

创伤性脑损伤（TBI）是一种疾病，外力正常脑功能受损。 TBI是 估计每年影响全球约6900万人。轻度TBI是最常见的脑损伤形式 （在所有情况的〜70-90％），以几乎没有时间的无意识和最小的可观察缺陷为特征 立即受伤后。轻度脑损伤通常归因于参与接触运动（例如拳击， 足球，足球，曲棍球），兵役，以及亲密的伴侣暴力。甚至温和的TBI，尤其是 反复受伤后，急性和长期后果，包括增加的风险 中风和痴呆症。鉴于明确的证据表明TBI增加了以后的痴呆症的风险，这是很棒的 兴趣确定驱动不同类型TBI与各种关系之间关系的机制 与痴呆相关的神经病理学，因此可以确定干预靶标。重复的轻度TBI具有 最显着与慢性创伤性脑病（一种tauopathy）有关，尽管一些证据 表明它也可能有助于阿尔茨海默氏症和其他神经退行性疾病。但是，少知道 关于脑淀粉样血管病（CAA）是否也可能是将TBI与痴呆联系起来的机制。 CAA是 淀粉样蛋白（最常见的是β-淀粉样蛋白的积累，与阿尔茨海默氏病有关） 脑血管系统，导致痴呆风险增加[两种血管对认知的贡献 障碍和痴呆（VCID）和阿尔茨海默氏病]以及缺血性和出血性中风。 在以前的运动员中观察到CAA水平的升高，他们往往具有重复性轻度大脑的病史 受伤。需要使用动物模型的实验设计来确定是否重复中间 TBI影响CAA和相关病理的主动性和进展。在这里，我们将受到TG-SWDI小鼠的影响 （CAA的转基因小鼠模型）从〜2个月开始重复轻度TBI（连续5天1x/天） 年龄。这个年龄大致相当于青少年晚期/年轻的成年期，当时TBI最常见，并且是 在这种菌株中出现明显的CAA病理和认知障碍之前。然后我们将确定 在TBI之后两个时间点上，认知行为缺陷和神经病理学是否发生了变化（短期：7 天和长期：3个月）。此外，我们将研究生物学是否适中 重复的轻度TBI与CAA相关结果之间的关系。我们的长期目标是确定 将TBI和痴呆症风险增加的机制联系起来，这可能又可能显示出新的治疗目标。