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）是一种正常脑功能受到外力损害的情况。TBI为 据估计，每年全球约有6900万人受到影响。轻度脑外伤是最常见的脑损伤形式 （约占所有病例的70-90%），特征为几乎没有时间无意识和最小的可观察到的缺陷 受伤后立即轻度脑损伤通常归因于参与接触性运动（如拳击， 足球，足球，曲棍球），服兵役，并作为亲密伴侣暴力的结果。即使是轻微的外伤，尤其是 在反复受伤后，具有毁灭性的急性和长期后果，包括增加 中风和痴呆鉴于明确的证据表明，TBI增加了老年痴呆症的风险，这是很大的 感兴趣的是确定驱动不同类型的TBI和各种 痴呆相关的神经病理学，以便可以确定干预的目标。反复轻度TBI 最明显的是与慢性创伤性脑病（一种tau蛋白病）有关，尽管有一些证据表明， 表明它也可能导致阿尔茨海默氏症和其他神经退行性疾病。然而， 关于脑淀粉样血管病（CAA）是否也可能是TBI与痴呆症联系的机制。CAA是 淀粉样蛋白（最常见的是β-淀粉样蛋白，与阿尔茨海默病有关）的积累， 脑血管系统，导致痴呆症风险增加[血管对认知功能的贡献 损伤和痴呆（VCID）和阿尔茨海默病]，以及缺血性和出血性中风。 在前运动员中观察到CAA水平增加，他们往往有重复性轻度大脑 受伤需要使用动物模型进行实验设计，以确定是否以及如何重复轻度 TBI影响CAA及其相关病理的发生和发展。在这里，我们将Tg-SwDI小鼠 （CAA转基因小鼠模型）至重复性轻度TBI（1次/天，连续5天），从约2个月开始 年龄。这个年龄大致相当于青少年晚期/青年期，此时TBI最常见， 在该菌株中显著的CAA病理学和认知障碍发作之前。然后我们将决定 TBI后两个时间点的认知行为缺陷和神经病理学是否改变（短期：7 日和更长时间：3个月）。此外，我们将调查生物性别是否会调节 反复轻度TBI与CAA相关结局之间的关系。我们的长期目标是确定 TBI和痴呆风险增加的联系机制，这反过来可能揭示新的治疗靶点。