The Role of Monocytes and Microglia in Traumatic Brain Injury-Induced Tauopathies

描述(申请人提供)：创伤性脑损伤(TBI)是一种在美国平民和军人中非常常见的损伤，许多存活下来的人都患有与TBI相关的永久性残疾。值得注意的是，暴露于脑外伤的个人患上一系列神经退行性疾病的风险大大增加，这些疾病被称为tauopathy，包括阿尔茨海默病(AD)和慢性创伤性脑病(CTE)。更具体地说，在CTE和AD中，TBI促进过度磷酸化的微管相关蛋白tau(MAPT)在细胞内聚集成神经原纤维缠结(NFT)。颅脑损伤最早和最显著的特征之一是诱导神经炎症，包括外周血单核细胞渗入损伤部位和激活驻留的脑小胶质细胞。来自文献和我们实验室的几条证据表明，单核细胞浸润和小胶质细胞激活的改变可能直接参与了MAPT的病理机制。然而，由于缺乏可靠的方法来区分脑内单核细胞和激活的小胶质细胞，在MAPT病理的准确遗传模型中，评估这些细胞在脑损伤诱导的MAPT病理中的确切作用被证明是极其困难的。目前研究中要验证的主要假设是，脑外伤可诱导外周血单核细胞的渗透以及受损脑内脑小胶质细胞的急性和局部激活，并且这两种细胞在诱导MAPT磷酸化和聚集方面扮演着不同的角色，从而导致慢性病理条件，使暴露于脑损伤的人在以后的生活中容易患上自发性疾病。的目标 这项探索性研究拨款旨在利用独特的单核细胞(CCR2-RFP)和小胶质细胞(CX3CR1-GFP)荧光标记遗传模型、基于基因组的MAPT(HTau)病理模型和单核细胞渗透受阻的遗传模型(CCR2缺乏症)，评估浸润性单核细胞和激活的小胶质细胞在脑损伤后MAPT病理发展中的作用。这项研究的结果将对未来的临床前研究至关重要，这些研究旨在以单核细胞或小胶质细胞为治疗靶点，以阻断TBI对下游MAPT病理的影响。本研究的具体目的是：1.研究轻、中度脑创伤对对照组和hTau小鼠外周血单核细胞浸润、小胶质细胞活化和MAPT病理改变、认知功能及神经退行性变的影响。2.探讨浸润性单核细胞在脑创伤后MAPT病理过程中的作用。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a very common injury in civilian as well as military populations in the United States and a large number of those that survive live with permanent TBI related disabilities. Notably, individuals exposed to TBI are at a greatly increased risk for developing a number of neurodegenerative diseases termed tauopathies, including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). More specifically, TBI promotes the intracellular aggregation of hyperphosphorylated, microtubule- associated protein tau (MAPT) into neurofibrillary tangles (NFTs) in both CTE and AD. One of the earliest and hallmark features of TBI is induction of neuroinflammation, including infiltration of peripheral monocytes into the site of injury and activation of resident brain microglia. Several lines of evidence from the literature and from our laboratories suggest that altered monocyte infiltration and microglial activation may be directly involved in the pathogenesis of MAPT pathologies. However, assessing the exact role of these cells in TBI-induced MAPT pathologies has proven exceedingly difficult due to the lack of reliable methods to distinguish monocytes and activated microglia within the brain in accurate genetic models of MAPT pathologies. The primary hypothesis to be tested in the current studies is that TBI induces infiltration of peripheral monocytes as well as acute and local activation of brain microglia within the injured brain and that these two cell types play roles distinct from each othe in inducing MAPT phosphorylation and aggregation leading to chronic pathological conditions that pre-dispose individuals exposed to TBI to develop tauopathies later in life. The objectives of this exploratory research grant are to assess the role of infiltrating monocytes and activated microglia in the development of MAPT pathologies following TBI utilizing unique genetic models that fluorescently tag monocytes (CCR2-RFP) and microglia (CX3CR1-GFP), genomic-based mouse models of MAPT (hTau) pathologies and genetic models in which infiltration of monocytes is blocked (CCR2 deficiency). The results of this study will be critical for future preclinical studies designed to therapeutically target either monocytes or microglia to block the effects of TBI on downstream MAPT pathologies. The specific aims of the proposal are: 1. Determine the effect of both mild and moderate TBI on infiltration of peripheral monocytes, activation of microglia and MAPT pathology, cognitive function and neurodegeneration in control and hTau mice. 2. Determine the role of infiltrating monocytes in TBI Induced MAPT pathologies in hTau mice.