Delayed and Progressive Emergence of CTE- and Psychiatric-like Pathologies after Repetitive Mild TBI

项目摘要/摘要 创伤性脑损伤被称为近年来军事作战中的“标志性损伤”。 在伊拉克和阿富汗。在军人和退伍军人中最常见的脑损伤形式 是重复性的、轻度的脑损伤，或称rmTBI。除了头部损伤的直接影响外，rmTBI还与 有许多重大和慢性并存的疾病，包括认知功能障碍，睡眠障碍， 视功能改变和精神并发症(如抑郁、自杀、焦虑)。RmTBI及其ITS 共同的疾病给军事人员和退伍军人造成了巨大的损失，而TBI给国家带来的代价是 估计每年600亿美元。RmTBI改变脑功能的机制尚不清楚。 到目前为止，所有治疗脑损伤的新疗法的临床试验都失败了。因此，一个有效的治疗方法 因为TBI是不存在的。也许rmTBI最令人担忧的方面是反复轻微撞击的可能性 对头部不会引起临床上显著或可识别的症状，但会引发一系列的 神经退化和精神疾病的终点。这个应用程序的主要目标是1)改进 并验证rmTBI的人源化小鼠模型和2)测试两种新的基于机制的疗法 RmTBI的长期后果。这些目标将通过采用新的rmTBI模式来实现，即 非常轻微，即使在20次头部撞击后也不会导致任何行为或神经元 疗程结束时的病理学检查。我们包括的初步数据表明，rmTBI导致 白质束上反应性胶质增生和炎症增加的延迟和进行性出现， 病理形式的tau增加，tau是一种微管稳定分子。此外，这种模式的rmTBI 导致认知障碍和类似精神障碍的缓慢发展(例如，焦虑和抑郁)， 在rmTBI疗程结束后，这两种症状都不会立即显现。这些神经元和行为 结果是慢性创伤性脑病(CTE)的标志性征兆，已经在 暴露于rmTBI的军人的死后脑。两种新药将作为治疗药物进行测试 包括组蛋白脱乙酰酶6抑制物(HDAC6)和集落刺激因子1受体 (CSFR1)抑制中枢神经系统小胶质细胞。使用HDAC6抑制剂治疗 RmTBI之所以令人信服，有几个原因。首先，通过乙酰化修饰tau可以防止其聚集。 (即，其病理形式)通过抑制其磷酸化。其次，HDAC6已被确定为特定的 使tau脱乙酰化的酶。Tau的脱乙酰化允许通过磷酸化修饰tau。第三, 抑制HDAC6应该改变乙酰化/磷酸化的平衡，有利于乙酰化，从而 保护tau不受脑内病理性聚集的影响。使用CSF1R抑制剂的理由是 同样令人信服和强烈，因为rmTBI导致小胶质细胞激活显著增加， 然后导致星形胶质细胞的二次激活。这种增加的胶质细胞反应性导致神经元损伤。通过 去除小胶质细胞，CSF1R抑制剂应该阻止小胶质细胞和星形胶质细胞的激活，并减少 CTE中发生的类似CTE的损害。RmTBI的影响将在小鼠的慢性时间框架内进行研究，以 模拟人类重复头部后出现的缓慢发展的神经病理和行为障碍 受伤。治疗直到小鼠暴露在重复的头部撞击之后才会开始，以便模拟 临床情况更加密切。假设在rmTBI后抑制HDAC6或CSF1R将防止或 减少CTE样tau病变的发展。它进一步假设，防止形成的 使用这些治疗方法的肌萎缩侧索硬化症将减少高发的慢性合并症 RmTBI后的频率包括认知功能障碍，视力和睡眠的改变，以及抑郁-以及 焦虑性行为障碍。该项目对退伍军人管理局的医疗保健任务具有很高的翻译相关性。

Project Summary/Abstract Traumatic brain injury (TBI) has been referred to as the “signature injury” of recent military combat operations in Iraq and Afghanistan. The form of TBI that is most prevalent among military service members and Veterans is repetitive, mild TBI, or rmTBI. Apart from the immediate effects of a head injury, rmTBI is also associated with a number of significant and chronic co-morbid conditions including cognitive dysfunction, sleep disorders, alterations in visual function, and psychiatric complications (e.g., depression, suicide, anxiety). rmTBI and its co-morbid conditions exact a steep toll on military personnel and Veterans and the cost to the nation of TBI is estimated to be $60 billion annually. The mechanisms by which rmTBI alters brain function are not well understood and all clinical trials of new therapies for TBI thus far have failed. Therefore, an effective treatment for TBI does not exist. Perhaps the most alarming aspect of rmTBI is the possibility that repeated mild impacts to the head do not cause clinically significant or recognizable symptoms but set in motion a cascade which has an endpoint of neurodegeneration and psychiatric illness. The primary goals of this application are to 1) refine and validate a humanized mouse model of rmTBI and 2) test two new mechanism-based therapies for the long-term consequences of rmTBI. These goals will be achieved by employing a new model of rmTBI that is very mild, even after as many as 20 head impacts, and which does not result in any behavioral or neuronal pathology at the end of the treatment period. We include preliminary data showing that rmTBI results in a delayed and progressive emergence of increased reactive gliosis and inflammation along white matter tracts, and increases in the pathologic form of tau, a microtubule stabilizing molecule. In addition, this model of rmTBI results in slowly developing cognitive deficits and psychiatric-like disorders (e.g., anxiety and depression), neither of which are evident immediately after the rmTBI course of treatment. These neuronal and behavioral outcomes are hallmark signs of chronic traumatic encephalopathy (CTE) and have been observed in postmortem brains of military service members exposed to rmTBI. Two new drugs will be tested as therapies for rmTBI and include an inhibitor of histone deacetylase 6 (HDAC6) and a colony-stimulating factor 1 receptor (CSFR1) inhibitor that ablates CNS microglia. The rationale behind the use of an HDAC6 inhibitor for treating rmTBI is compelling for several reasons. First, modification of tau by acetylation protects it from aggregation (i.e., its pathological form) by inhibiting its phosphorylation. Second, HDAC6 has been identified as the specific enzyme that deacetylates tau. Deacetylation of tau allows for modification of tau by phosphorylation. Third, inhibition of HDAC6 should shift the balance of acetylation/phosphorylation to favor acetylation and thereby protect tau against pathological aggregation in brain. The rationale behind the use of a CSF1R inhibitor is likewise compelling and strong because rmTBI results in significant increases in microglial activation which then causes a secondary activation of astrocytes. This increased glial reactivity results in neuronal damage. By ablating microglia, a CSF1R inhibitor should prevent activation of both microglia and astrocytes and reduce the CTE-like damage that occurs in CTE. The effects of rmTBI will be studied over a chronic time-frame in mice to simulate the slow-developing neuropathologies and behavioral disorders seen in humans after repeated head injuries. Treatment will not begin until after exposure of mice to repetitive head impacts in order to simulate a clinical situation more closely. It is hypothesized that inhibition of HDAC6 or CSF1R after rmTBI will prevent or reduce the development of CTE-like tau pathology. It is hypothesized further that prevention of the formation of tauopathies with these treatments will reduce the chronic co-morbid conditions that develop with high frequency after rmTBI to include cognitive dysfunction, alterations in vision and sleep, and depression- and anxiety-like behavioral disorders. This project has high translational relevance for the VA health care mission.