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生的危险因素