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

项目总结/摘要 创伤性脑损伤（TBI）被称为近年来军事作战行动的“标志性损伤 在伊拉克和阿富汗。TBI的形式是最普遍的军人和退伍军人 是重复性轻度TBI或rmTBI。除了头部损伤的直接影响外，rmTBI还与 患有许多严重的慢性共病，包括认知功能障碍，睡眠障碍， 视觉功能的改变，和精神并发症（例如，抑郁、自杀、焦虑）。rmTBI及其 共病的条件精确的军事人员和退伍军人和成本的TBI国家是陡峭的收费 估计每年600亿美元。rmTBI改变脑功能的机制尚不清楚 目前为止，所有针对TBI的新疗法的临床试验都失败了。因此，有效的治疗 TBI不存在。也许rmTBI最令人担忧的方面是重复的轻微撞击 头部的疼痛不会引起临床上显著或可识别的症状，但会引起级联反应， 神经退化和精神疾病的终点。此应用程序的主要目标是：1）细化 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治疗方法， RmTBI的长期后果。这些目标将通过采用一种新的rmTBI模式来实现， 非常轻微，即使在多达20次头部撞击后，也不会导致任何行为或神经元损伤。 在治疗期结束时进行病理学检查。我们包括初步数据显示，rmTBI的结果， 延迟和进行性出现沿着白色束的反应性神经胶质增生和炎症增加， 并增加病理形式的tau，一种微管稳定分子。此外，这种rmTBI模型 导致缓慢发展的认知缺陷和精神病样障碍（例如，焦虑和抑郁）， 在rmTBI治疗过程后，这两种情况都不明显。这些神经元和行为 结果是慢性创伤性脑病（CTE）的标志性体征， 暴露于rmTBI的军人死后的大脑。两种新药将作为治疗方法进行测试 用于rmTBI，包括组蛋白脱乙酰酶6（HDAC 6）抑制剂和集落刺激因子1受体 （CSFR 1）抑制剂，其消融CNS小胶质细胞。使用HDAC 6抑制剂治疗糖尿病的基本原理 rmTBI是令人信服的几个原因。首先，通过乙酰化修饰tau蛋白可保护其免于聚集 (i.e.,其病理形式）通过抑制其磷酸化。其次，HDAC 6已被确定为特定的 使tau蛋白脱乙酰基的酶。tau的脱乙酰化允许通过磷酸化修饰tau。第三、 HDAC 6的抑制应该使乙酰化/磷酸化的平衡向有利于乙酰化的方向移动， 保护tau蛋白免受脑内病理性聚集。使用CSF 1 R抑制剂的基本原理是 同样令人信服和强大，因为rmTBI导致小胶质细胞激活的显着增加， 然后引起星形胶质细胞的二次激活。这种增加的神经胶质反应性导致神经元损伤。通过 切除小胶质细胞，CSF 1 R抑制剂应该防止小胶质细胞和星形胶质细胞的激活，并减少 CTE中发生的CTE样损伤。将在小鼠中研究rmTBI的长期作用， 模拟人类在反复头部后出现的缓慢发展的神经病理和行为障碍， 受伤处理将开始，直到小鼠暴露于重复的头部撞击之后，以模拟 临床情况更加密切。假设在rmTBI后抑制HDAC 6或CSF 1 R将预防或减少脑损伤。 减少CTE样tau病理学的发展。进一步假设，预防形成 使用这些治疗的tau蛋白病将减少与高表达的tau蛋白相关的慢性共病状况。 rmTBI后的频率，包括认知功能障碍，视力和睡眠的改变，以及抑郁症-和 类似焦虑的行为障碍该项目对退伍军人管理局的医疗保健使命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.