Neurodegeneration following low-level blast exposure

低水平爆炸暴露后的神经变性

• 批准号: 10269000
• 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/10269000
• 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; active duty; age related; age related cognitive change; base; behavior test; behavioral impairment; behavioral phenotyping; blast exposure; 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; military veteran; 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）是发展神经退行性疾病的危险因素，其中 认知障碍是显着的，包括阿尔茨海默氏病和慢性创伤性脑病（CTE）。 由于最近在伊拉克和阿富汗发生冲突中，由于爆炸曝光引起的轻度TBI（MTBI）的高流行率 使退伍军人面临着这些疾病的风险。有趣的是，暴露于重复低级爆炸的雄性大鼠 暴露表现出慢性行为表型，其中包括动画和创伤后压力的元素 疾病（PTSD）相关的行为特征，与大脑中的高磷酸化tau相关。 爆炸后几个月以及微管结合蛋白质蛋白1的慢性升高1。 这两个关键的微管结合蛋白的改变，表明重复的爆炸暴露可能 从根本上改变了微管网络，这可能与 神经退行性条件，例如CTE。这些研究将确定低 - 的影响时间过程 使用细胞分流策略和 使用针对磷酸化tau的抗体面板进行生化分析。其他微管的水平 将检查关联的蛋白质，包括毒药1，以及微管的组装状态 随着时间的推移。爆炸暴露的大鼠还会在海马中出现树突状脊柱损失。爆炸的时间课程 对树突状脊柱密度，每单位长度，脊柱类型和脊柱体积的树突状脊柱数量的影响 使用定量的立体原则确定自旋素免疫抑制部分和3D重建图像 路西法黄的神经元。电子显微镜将用于评估树突状的超微结构 刺和微管。测试是否与重复低级相关的慢性行为效应是否相关 爆炸暴露在机械上与对微管稳定性的影响有关 微管稳定剂Epothilone D可以逆转爆炸损伤后的慢性行为效应。它 还将确定行为变化是否持续还是随着爆炸暴露后的衰老而进展 而且，尤其是与年龄相关的认知变化是否出现。分子和 采用行为和认知测试的形态学研究将进一步深入了解 爆炸引起的损伤。一组研究将决定雌性大鼠是否发展与爆炸有关 表型，迄今为止仅在雄性大鼠中研究了。拟议的研究集体将 探索潜在的目标，以治疗现役军事人员的爆炸引起的脑损伤 受这些潜在毁灭性伤害影响的退伍军人。

项目成果

Transcranial Laser Therapy Does Not Improve Cognitive and Post-Traumatic Stress Disorder-Related Behavioral Traits in Rats Exposed to Repetitive Low-Level Blast Injury.

• DOI: 10.1089/neur.2021.0005
• 发表时间: 2021
• 期刊: Neurotrauma reports
• 影响因子: 2.4
• 作者: Perez Garcia G;Perez GM;Otero-Pagan A;Abutarboush R;Kawoos U;De Gasperi R;Gama Sosa MA;Pryor D;Hof PR;Cook DG;Gandy S;Ahlers ST;Elder GA
• 通讯作者: Elder GA

BCI-838, an orally active mGluR2/3 receptor antagonist pro-drug, rescues learning behavior deficits in the PS19 MAPTP301S mouse model of tauopathy.

BCI-838 是一种口服活性 mGluR2/3 受体拮抗剂前药，可挽救 PS19 MAPTP301S tau 蛋白病小鼠模型的学习行为缺陷。

• DOI: 10.1016/j.neulet.2023.137080
• 发表时间: 2023
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Perez-Garcia,Georgina;Bicak,Mesude;Haure-Mirande,Jean-Vianney;Perez,GisselM;Otero-Pagan,Alena;GamaSosa,MiguelA;DeGasperi,Rita;Sano,Mary;Barlow,Carrolee;Gage,FredH;Readhead,Benjamin;Ehrlich,MichelleE;Gandy,Sam;Elder,Gregory
• 通讯作者: Elder,Gregory

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury.

• DOI: 10.1089/neur.2022.0088
• 发表时间: 2023
• 期刊: NEUROTRAUMA REPORTS
• 影响因子: 2.4
• 作者: Garcia, Georgina Perez;Perez, Gissel M. M.;De Gasperi, Rita;Sosa, Miguel A. Gama;Otero-Pagan, Alena;Abutarboush, Rania;Kawoos, Usmah;Statz, Jonathan K. K.;Patterson, Jacob;Zhu, Carolyn W. W.;Hof, Patrick R. R.;Cook, David G. G.;Ahlers, Stephen T. T.;Elder, Gregory A. A.
• 通讯作者: Elder, Gregory A. A.

Blast-Related Mild TBI Alters Anxiety-Like Behavior and Transcriptional Signatures in the Rat Amygdala.

• DOI: 10.3389/fnbeh.2020.00160
• 发表时间: 2020
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Blaze J;Choi I;Wang Z;Umali M;Mendelev N;Tschiffely AE;Ahlers ST;Elder GA;Ge Y;Haghighi F
• 通讯作者: Haghighi F

Unconventional animal models for traumatic brain injury and chronic traumatic encephalopathy.

• DOI: 10.1002/jnr.24920
• 发表时间: 2021-10
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Ackermans NL;Varghese M;Wicinski B;Torres J;De Gasperi R;Pryor D;Elder GA;Gama Sosa MA;Reidenberg JS;Williams TM;Hof PR
• 通讯作者: Hof PR