Neurodegeneration following low-level blast exposure

低水平爆炸暴露后的神经变性

• 批准号: 9757616
• 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/9757616
• 关键词: 3-Dimensional; Affect; Afghanistan; Aging; Alzheimer' s Disease; Amygdaloid structure; Animal Model; Antibodies; Anxiety; Axon; Behavioral; Binding Proteins; Biochemical; 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; Sex Differences; 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; behavioral phenotyping; 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; severe injury; 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（TBI）是神经退行性疾病发展的危险因素，其中 认知障碍很突出，包括阿尔茨海默病和慢性创伤性脑病（CTE）。 由于近期伊拉克和阿富汗冲突中的爆炸暴露，轻度 TBI (mTBI) 的患病率很高 使退伍军人患这些疾病的风险增加。有趣的是，雄性老鼠暴露于重复的低强度爆炸中 暴露表现出慢性行为表型，包括焦虑和创伤后应激因素 与 10 岁时大脑中 tau 蛋白过度磷酸化相关的精神障碍 (PTSD) 相关行为特征 爆炸后几个月的暴露以及微管结合蛋白 Stathmin 1 的慢性升高。 这两种关键微管结合蛋白的改变表明重复的爆炸暴露可能 从根本上改变微管网络，这可能与 神经退行性疾病，例如 CTE。这些研究将确定低影响的时间进程 使用细胞亚分级策略对 tau 磷酸化和加工进行水平爆炸暴露 使用一组抗磷酸化 tau 抗体进行生化分析。其他微管的水平- 将检查相关蛋白，包括 Stathmin 1 以及微管的组装状态 随着时间的推移。暴露于爆炸的大鼠的海马体也会出现树突棘缺失。爆炸的时间进程 对树突棘密度、每单位长度的树突棘数量、树突棘类型和树突棘体积的影响将是 使用定量体视学对亲旋蛋白免疫染色切片和 3D 重建图像进行测定 负载路西法黄的神经元。电子显微镜将用于评估树突的超微结构 刺和微管。测试慢性行为影响是否与重复的低水平相关 爆炸暴露在机制上与微管稳定性的影响有关，我们将确定是否 微管稳定剂埃坡霉素 D 可以逆转爆炸损伤后的慢性行为影响。它 还将确定爆炸暴露后行为变化是否持续存在或随着衰老而进展 特别是是否出现与年龄相关的认知变化。分子和的相关性 行为和认知测试的形态学研究将进一步深入了解 爆炸引起的伤害。一组平行研究将确定雌性大鼠是否会出现与爆炸相关的疾病 表型，迄今为止仅在雄性大鼠中进行了研究。总的来说，拟议的研究将 探索治疗现役军人爆炸性脑损伤的潜在目标 受到这些潜在毁灭性伤害影响的退伍军人。