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）在美国平民和军人中是一种非常常见的伤害，许多幸存者都患有永久性的TBI相关残疾。值得注意的是，暴露于创伤性脑损伤的个体患许多神经退行性疾病的风险大大增加，这些疾病被称为tau病，包括阿尔茨海默病（AD）和慢性创伤性脑病（CTE）。更具体地说，TBI促进CTE和AD中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）。TBI的早期和标志性特征之一是神经炎症的诱导，包括外周单核细胞浸润到损伤部位和驻留的脑小胶质细胞的激活。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活化的改变可能直接参与了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非常困难的，因为在准确的MAPT病理遗传模型中缺乏可靠的方法来区分大脑内的单核细胞和活化的小胶质细胞。目前研究中需要验证的主要假设是，创伤性脑损伤诱导外周单核细胞浸润以及损伤脑内脑小胶质细胞的急性和局部激活，这两种细胞类型在诱导MAPT磷酸化和聚集方面发挥着不同的作用，导致慢性病理状况，使暴露于创伤性脑损伤的个体在以后的生活中容易发生tau病。的目标

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.