Neurodegeneration following low-level blast exposure

创伤性脑损伤（TBI）是神经退行性疾病发展的危险因素， 认知障碍是突出的，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，由于爆炸暴露导致轻度TBI（mTBI）的高患病率 使退伍军人患这些疾病的风险增加。有趣的是，暴露于重复性低强度爆炸的雄性大鼠 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岁时大脑中过度磷酸化tau蛋白相关的PTSD相关行为特征 爆炸后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，重复的冲击波暴露可能 从根本上改变微管网络，这可能与发展有关， 神经退行性疾病，如CTE。这些研究将确定低- 使用细胞亚分级策略对tau蛋白磷酸化和加工进行水平冲击暴露， 用一组抗磷酸化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查 随着时间冲击波暴露的大鼠也发展海马树突棘损失。爆炸时程 对树突棘密度、单位长度树突棘数量、棘类型和棘体积的影响将被 使用定量体视学在spinophilin免疫染色切片和3D重建图像上测定 路西法黄负载的神经元。电镜观察树突状细胞的超微结构 刺和微管。为了测试是否与重复性低水平运动相关的慢性行为效应 冲击波暴露与微管稳定性的影响机制相关，我们将确定 微管稳定剂埃坡霉素D可以逆转冲击伤后的慢性行为效应。它 还将确定在爆炸暴露后，行为变化是否会随着年龄的增长而持续或进展 尤其是是否出现与年龄相关的认知变化。分子和 形态学研究与行为和认知测试将提供进一步的洞察机制， 爆炸造成的伤害一组平行的研究将确定雌性大鼠是否会发展出与爆炸有关的 表型，迄今为止仅在雄性大鼠中进行了研究。总体而言，拟议的研究将 探索现役军人爆炸性脑损伤治疗的潜在靶点， 受这些潜在的毁灭性伤害影响的退伍军人。

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.