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

描述（由申请人提供）：创伤性脑损伤（TBI）是美国平民和军人中非常常见的损伤，并且大量幸存者患有与TBI相关的永久性残疾。值得注意的是，暴露于TBI的个体发生许多称为tau蛋白病的神经退行性疾病的风险大大增加，包括阿尔茨海默病（AD）和慢性创伤性脑病（CTE）。更具体地，TBI促进CTE和AD中过度磷酸化的微管相关蛋白tau（MAPT）的细胞内聚集成神经元缠结（NFT）。TBI的最早和标志性特征之一是诱导神经炎症，包括外周单核细胞浸润到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，改变的单核细胞浸润和小胶质细胞活化可能直接参与MAPT病理的发病机制。然而，评估这些细胞在TBI诱导的MAPT病理中的确切作用已被证明是极其困难的，因为缺乏可靠的方法来区分MAPT病理的准确遗传模型中的脑内单核细胞和活化的小胶质细胞。在当前研究中待测试的主要假设是TBI诱导外周单核细胞的浸润以及损伤脑内脑小胶质细胞的急性和局部活化，并且这两种细胞类型在诱导MAPT磷酸化和聚集中发挥彼此不同的作用，导致慢性病理状况，所述慢性病理状况使暴露于TBI的个体在以后的生活中易患tau蛋白病。的目标 这项探索性研究资助是为了评估浸润的单核细胞和活化的小胶质细胞在TBI后MAPT病理学发展中的作用，利用荧光标记单核细胞（CCR 2-RFP）和小胶质细胞（CX 3CR 1-GFP）的独特遗传模型，MAPT（hTau）病理学的基于基因组的小鼠模型和单核细胞浸润被阻断（CCR 2缺陷）的遗传模型。这项研究的结果将是至关重要的未来临床前研究，旨在治疗靶向单核细胞或小胶质细胞，以阻止TBI对下游MAPT病理的影响。该提案的具体目标是：1。确定轻度和中度TBI对对照和hTau小鼠中外周单核细胞浸润、小胶质细胞活化和MAPT病理学、认知功能和神经变性的影响。2.确定浸润单核细胞在hTau小鼠中TBI诱导的MAPT病理中的作用。

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.