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

创伤性脑损伤是指正常的脑功能受到外力的影响。TBI是 据估计，每年全球约有6900万人受到影响。轻度颅脑损伤是最常见的脑损伤形式 (约占所有病例的70%-90%)，特点是极少或根本没有时间潜意识和最小的可观察缺陷 伤后即刻。轻微的脑损伤通常归因于参加接触性运动(例如拳击， 足球、足球、曲棍球)、服兵役以及亲密伴侣的暴力行为。即使是轻微的脑外伤，尤其是 在反复受伤后，会产生破坏性的严重和长期后果，包括增加 中风和痴呆症。鉴于明确的证据表明，脑外伤会增加晚年患痴呆症的风险，这是非常有意义的 有兴趣确定驱动不同类型脑损伤和不同类型脑损伤之间关系的机制 痴呆症相关的神经病理学，以便确定干预的目标。重复性轻度颅脑损伤 最明显的与慢性创伤性脑病(一种牵引性脑病)有关，尽管有一些证据 这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，鲜为人知的是 脑淀粉样血管病(CAA)是否也可能是脑外伤与痴呆之间的联系机制。CAA是 淀粉样蛋白(最常见的β-淀粉样蛋白，与阿尔茨海默病有关)在 脑血管系统，导致痴呆症风险增加[这两种血管对认知的贡献 损害和痴呆(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水平升高，他们往往有反复轻度脑部疾病的病史 受伤。需要使用动物模型的实验设计来确定是否以及如何重复性轻微 颅脑损伤影响CAA的发生、发展及相关病理。在这里，我们将让TG-Swdi小鼠 (CAA转基因小鼠模型)从~2个月开始重复轻度脑损伤(每天1次，连续5天) 年纪大了。这个年龄大致相当于青春期后期/青春期，此时脑外伤最常见， 在这种菌株出现显著的CAA病理和认知障碍之前。然后我们将确定 脑损伤后两个时间点认知行为障碍和神经病理是否发生改变(短期：7 天数及更长期：3个月)。此外，我们将调查生物性行为是否会缓和 重复性轻度颅脑损伤与CAA相关预后的关系。我们的长期目标是确定 将脑外伤与痴呆风险增加联系起来的机制，这反过来可能揭示新的治疗靶点。

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.