The role of microglia in acute pathology of repeated concussion and CTE development

小胶质细胞在反复脑震荡和 CTE 发展的急性病理学中的作用

• 批准号: 8932608
• 负责人: AMANDA BOLTON-HALL
• 金额: $ 2.75万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932608
• 关键词: Acute; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Appearance; Astrocytes; Astrocytosis; Athletic; Attenuated; Behavioral; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Concussion; Brain Injuries; Case Study; Cell Death; Cessation of life; Chronic; Clinical; Closed head injuries; DNA-Binding Proteins; Data; Development; Diagnosis; Enzyme-Linked Immunosorbent Assay; Exhibits; Functional disorder; Goals; Human; Ibuprofen; Individual; Inflammation; Inflammatory Response; Injury; Knowledge; Laboratories; Lead; Learning; Link; Mediator of activation protein; Memory; Memory impairment; Microglia; Military Personnel; Modeling; Molecular; Molecular Profiling; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Pathology; Penetrating Brain Injury; Pharmaceutical Preparations; Phosphotransferases; Progranulin; Proteins; Randomized; Reporting; Risk; Rodent Model; Role; Sports; Stab Wounds; Symptoms; Testing; Therapeutic Intervention; Time; Tissues; Training; Traumatic Brain Injury; United States; Western Blotting; age related; anxiety-like behavior; astrogliosis; axon injury; behavior test; catalyst; chronic traumatic encephalopathy; combat; cytokine; cytotoxic; early onset; high risk; hyperphosphorylated tau; in vivo; injured; innovation; mild traumatic brain injury; motor deficit; mouse model; neurobehavioral; neuropathology; novel; progressive neurodegeneration; public health relevance; repaired; response; tau aggregation; tau-1; tool

DESCRIPTION (provided by applicant): In the United States, 70-90% of the approximately 1.7-3.8 million traumatic brain injuries (TBI) reported every year are considered "mild" and result in a wide range of acute symptoms, the cause of which are not well understood. Individuals involved in activities such as the military and athletics are at increased risk of accruing multipl TBIs. Due to natural variability involved in cases of repeated concussions in humans, animal models are instrumental in expanding our knowledge regarding the cellular consequences of mild TBI, which can include axonal injury, astrocytosis and microgliosis. Acute microglial activation may contribute to early tissue damage but has also been observed chronically after TBI and in many cases of neurodegenerative diseases where neurobehavioral consequences are evident. However, to our knowledge, no studies have focused on how microglia activation specifically affects the pathological outcomes of repeated mild TBI. We have developed a closed head injury (CHI) mouse model of concussion in which repeated concussive impacts, but not a single impact, result in acute microglial activation that is associated with greater neuron death and astrogliosis. To better understand the role of microglia in the pathology of repeated concussion, posttraumatic microgliosis will be amplified or attenuated in Aim 1. Progranulin-deficient (GRN KO) mice, which exhibit increased microgliosis compared to wildtype (WT) mice after a stab wound to the brain, will be used to elicit an enhanced microglial response after three concussions delivered at 24h inter-injury intervals. Ibuprofen, a common anti-inflammatory drug, will be given to a subset of WT mice after each injury to attenuate the normal CHI-induced microglial response. Memory, motor coordination, and anxiety-like behaviors, as well as axonal injury, neuronal degeneration, and astrocytosis will be evaluated in these three groups over the first 2 weeks after injury to test the hypothesis that neuropathological damage is proportional to early microglial activation. Persistent microgliosis is associated with a condition of progressive neurodegeneration after repeated mild TBI, termed chronic traumatic encephalopathy (CTE). CTE is officially diagnosed by cytosolic accumulations of phosphorylated TAR DNA binding protein 43 (pTDP43) and hyperphosphorylated Tau in the post-mortem brain. Currently, no animal model of TBI replicates all of these key pathological hallmarks, hindering progress in understanding the causative cellular and molecular factors underlying CTE. GRN KO mice have an age- dependent increase in microgliosis (~7mo) in the absence of injury that precedes the accumulation of pTDP43 (~12-18mo). In Aim 2, chronic histopathological and behavioral effects of repeated concussions will be compared in GRN KO and WT mice over time. We anticipate that persistent activation of microglia in brain- injured GRN KO mice will accelerate pTDP43 accumulation and worsen behavioral deficits, providing a more rapid and efficient model for assessing the links between repeated concussions and the development of CTE pathology. An animal model of CTE will also provide a platform for testing therapeutic interventions.

描述（由申请人提供）：在美国，每年报告的约170 - 380万例创伤性脑损伤（TBI）中有70-90%被认为是“轻度”， 在广泛的急性症状中，其原因尚不清楚。参与军事和体育等活动的个人患多发性TBI的风险增加。由于人类反复脑震荡病例中涉及的自然变异性，动物模型有助于扩大我们对轻度TBI细胞后果的了解，其中包括轴突损伤，星形胶质细胞增生和小胶质细胞增生。急性小胶质细胞活化可能导致早期组织损伤，但也在TBI后长期观察到，并且在许多神经行为后果明显的神经退行性疾病病例中观察到。然而，据我们所知，没有研究集中在小胶质细胞活化如何具体影响反复轻度TBI的病理结果。我们已经开发了一种闭合性脑损伤（CHI）小鼠脑震荡模型，其中反复的脑震荡冲击，但不是单一的冲击，导致急性小胶质细胞激活，这与更大的神经元死亡和星形胶质细胞增生。为了更好地理解小胶质细胞在反复脑震荡病理学中的作用，目标1中将放大或减弱创伤后小胶质细胞增生。前粒蛋白缺陷型（GRN KO）小鼠在脑刺伤后与野生型（WT）小鼠相比表现出增加的小神经胶质细胞增生，将用于在三次刺激后引起增强的小神经胶质细胞应答。 脑震荡在24小时的损伤间隔。在每次损伤后，将对WT小鼠的一个亚组给予一种常见的抗炎药物Iceland，以减弱正常的CHI诱导的小胶质细胞反应。在损伤后的前2周内，将在这三个组中评价记忆、运动协调和焦虑样行为，以及轴突损伤、神经元变性和星形细胞增多，以检验神经病理学损伤与早期小胶质细胞活化成比例的假设。持续性小胶质细胞增生与反复轻度TBI后的进行性神经变性相关，称为慢性创伤性脑病（CTE）。CTE通过死后脑中磷酸化的TAR DNA结合蛋白43（pTDP 43）和过度磷酸化的Tau的细胞溶质积累来正式诊断。目前，没有TBI的动物模型复制所有这些关键的病理特征，阻碍了对CTE的致病细胞和分子因素的理解。GRN K 0小鼠在没有损伤的情况下具有小神经胶质增生的年龄依赖性增加（约7个月），其先于pTDP 43的积累（约12- 18个月）。在目标2中，将在GRN KO和WT小鼠中随时间比较反复脑震荡的慢性组织病理学和行为效应。我们预期，脑损伤的GRN KO小鼠中小胶质细胞的持续活化将加速pTDP 43积累并恶化行为缺陷，从而为评估反复脑震荡与CTE病理学发展之间的联系提供更快速和有效的模型。CTE的动物模型也将提供用于测试治疗干预的平台。