Neurodegeneration following low-level blast exposure

低水平爆炸暴露后的神经变性

• 批准号: 9609816
• 负责人: Gregory A. Elder
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9609816
• 关键词: Affect; Afghanistan; Aging; Alzheimer' s Disease; Amygdaloid structure; Animal Model; Antibodies; Anxiety; Axon; Behavioral; Binding Proteins; Biochemical; Blast Cell; Blast Injuries; Brain; Brain Injuries; Chronic; Cognition; Conflict (Psychology); Dendrites; Dendritic Spines; Development; Electron Microscopy; Elements; Exhibits; Exposure to; Female; Frequencies; High Prevalence; Hippocampus (Brain); Human; Image; Immunohistochemistry; Impaired cognition; Injury; Iraq; Lead; Length; Long-Evans Rats; Medial; Microtubule stabilizing agent; Microtubule-Associated Proteins; Microtubules; Military Personnel; Modeling; Molecular; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Phenotype; Phosphorylation; Post-Traumatic Stress Disorders; Prefrontal Cortex; Rattus; Reporting; Risk; Risk Factors; Severities; Sorting - Cell Movement; Structure; Tauopathies; Testing; Time; Transgenic Mice; Trauma; Traumatic Brain Injury; Vertebral column; Veterans; Work; age related; age related cognitive change; base; behavior test; behavioral impairment; brain tissue; chronic traumatic encephalopathy; cognitive change; cognitive testing; density; disorder risk; epothilone D; human model; hyperphosphorylated tau; insight; lucifer yellow; male; mild traumatic brain injury; response; sex; spinophilin; stathmin; stress related disorder; synaptic function; tau Proteins; tau phosphorylation; tau-1; therapy design; trait; treatment strategy

Traumatic brain injury (TBI) is a risk factor for the development of neurodegenerative diseases in which cognitive impairment is prominent, including Alzheimer’s disease and chronic traumatic encephalopathy (CTE). The high prevalence of mild TBI (mTBI) due to blast exposure in the recent conflicts in Iraq and Afghanistan puts veterans at increased risk of these disorders. Interestingly, male rats exposed to repetitive low-level blast exposures exhibit a chronic behavioral phenotype that includes elements of anxiety and post-traumatic stress disorder (PTSD)-related behavioral traits that are associated with hyperphosphorylated tau in brain at 10 months post-blast exposure as well as chronic elevation of the microtubule-binding protein stathmin 1. Alterations in these two key microtubule-binding proteins suggest that repetitive blast exposure may fundamentally alter microtubular networks, which could be of relevance to the development of neurodegenerative conditions such as CTE. These studies will determine the time course of the effects of low- level blast exposure on tau phosphorylation and processing using a cellular subfractionation strategy and biochemical analyses with a panel of antibodies against phosphorylated tau. Levels of other microtubule- associated proteins, including stathmin 1, together with the assembly status of microtubules will be examined over time. Blast-exposed rats also develop dendritic spine loss in the hippocampus. The time course of blast effects on dendritic spine density, dendritic spine number per unit length, spine type, and spine volume will be determined using quantitative stereology on spinophilin-immunostained sections and 3D reconstructed images of Lucifer Yellow-loaded neurons. Electron microscopy will be used to assess the ultrastructure of dendritic spines and microtubules. To test whether the chronic behavioral effects associated with repetitive low-level blast exposure are mechanistically related to effects on microtubule stability we will determine whether the microtubule stabilizing agent epothilone D can reverse the chronic behavioral effects that follow blast injury. It will also be determined whether behavioral changes persist or progress with aging following blast exposure and, in particular, whether age-related cognitive changes appear. Correlation of the molecular and morphological studies with the behavioral and cognitive tests will provide further insight into the mechanisms of blast-induced injury. A parallel set of studies will determine whether female rats develop a blast-related phenotype, which to date has only been studied in male rats. Collectively, the proposed studies will explore potential targets for the treatment of blast-induced brain injury in active duty military personnel and veterans affected by these potentially devastating injuries.

创伤性脑损伤是神经退行性疾病的危险因素，在这种疾病中 认知障碍突出，包括阿尔茨海默病和慢性创伤性脑病(CTE)。 在最近的伊拉克和阿富汗冲突中，由于爆炸暴露而导致的轻度脑损伤(MTBI)的高流行率 使退伍军人患这些疾病的风险增加。有趣的是，雄性大鼠暴露在重复的低水平冲击波中 暴露显示出一种慢性行为表型，其中包括焦虑和创伤后应激 精神障碍(PTSD)相关行为特征与10岁时大脑中过度磷酸化tau相关 爆炸暴露后几个月以及微管结合蛋白stathmin1的慢性升高。 这两个关键微管结合蛋白的变化表明，重复冲击波暴露可能 从根本上改变微管网络，这可能与糖尿病的发展有关 神经退行性疾病，如CTE。这些研究将确定低血压影响的时间进程。 水平冲击波暴露对tau的磷酸化和使用细胞亚分级策略的处理和 用一组针对磷酸化tau的抗体进行生化分析。其他微管的水平- 相关的蛋白质，包括stathmin 1，以及微管的组装状态将被检测。 随着时间的推移。冲击波暴露的大鼠还会在海马区出现树突棘丢失。爆炸的时间进程 对树突棘密度、单位长度树突棘数量、脊椎类型和脊椎体积的影响 用定量体视学对SPIN免疫染色切片和3D重建图像进行测定 含有路西法·黄色的神经元。将使用电子显微镜来评估树枝状组织的超微结构 刺和微管。测试慢性行为效应是否与重复的低水平有关 冲击波暴露在力学上与微管稳定性的影响有关，我们将确定 微管稳定剂Epothilone D可逆转冲击伤后的慢性行为效应。它 还将确定爆炸暴露后的行为变化是持续的还是随着年龄的增长而进展 尤其是，是否会出现与年龄相关的认知变化。分子与分子间的关联 形态研究与行为和认知测试将提供进一步的洞察机制 爆炸致伤。一组平行的研究将确定雌性大鼠是否会发展成与爆炸相关的 表型，到目前为止只在雄性大鼠中进行了研究。总的来说，拟议的研究将 探索现役军人冲击性脑损伤治疗的潜在靶点 受这些潜在毁灭性伤害影响的退伍军人。