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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）是指正常脑功能因外力而受损的病症。据估计，轻度 TBI 每年影响约 6900 万人，是最常见的脑损伤形式。（约占所有病例的 70-90%），其特点是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发生的轻度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，甚至是亲密伴侣暴力造成的，尤其是轻微的创伤性脑损伤。反复受伤后，会产生毁灭性的急性和长期后果，包括增加受伤的风险鉴于有明确证据表明创伤性脑损伤会增加晚年患痴呆症的风险，这一点具有重要意义。有兴趣确定驱动不同类型 TBI 和各种疾病之间关系的机制痴呆相关的神经病理学，以便可以确定重复性轻度 TBI 的干预目标。与慢性创伤性脑病（一种 tau 蛋白病）最显着相关，尽管有一些证据表明它也可能导致阿尔茨海默病和其他神经退行性疾病，但人们知之甚少。脑淀粉样血管病 (CAA) 是否也可能是 TBI 与痴呆之间的联系机制。淀粉样蛋白（最常见的是β-淀粉样蛋白，与阿尔茨海默病相关）的积累脑血管系统，导致痴呆风险增加[血管对认知的贡献损伤和痴呆（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 水平升高，他们往往有重复性轻度脑部疾病史需要使用动物模型进行实验设计来确定是否以及如何重复轻度损伤。 TBI 影响 CAA 和相关病理学的发生和进展在这里，我们将对 Tg-SwDI 小鼠进行研究。（CAA 转基因小鼠模型）到从约 2 个月开始重复轻度 TBI（每天 1 次，连续 5 天）这个年龄大致相当于青春期后期/青年期，此时 TBI 最常见，并且是然后我们将确定该菌株出现显着的 CAA 病理和认知障碍之前。认知行为缺陷和神经病理学是否在 TBI 后的两个时间点发生改变（短期：7 天和更长期：3个月）此外，我们将调查生物性别是否会调节。我们的长期目标是确定重复性轻度 TBI 与 CAA 相关结果之间的关系。 TBI 与痴呆风险增加之间存在联系，这可能反过来揭示新的治疗靶点。