Aging exacerbates trauma-induced immune pathways and neuronal dysfunction

项目摘要 创伤性脑损伤（TBI）对老龄化社区来说极其虚弱，发病率增加， 这一人群中的严重后果。此外，创伤性脑损伤是发展的一个强有力的环境风险因素 老年痴呆症和其他痴呆相关疾病。年龄作为预后因素的重要性 TBI早已被认识到，但有限的研究致力于了解调节TBI的机制。 在最初创伤后发生的继发性事件。更少的研究旨在研究 老年人认知功能丧失的机制。影响认知的关键变化发生在很长一段时间内， 初始损伤和先天免疫系统激活后的一段时间是关键的继发性损伤 导致慢性神经变性和神经功能丧失的机制。在本提案中，我们 将研究浸润性巨噬细胞和活化的常驻小胶质细胞在 产生神经毒性和炎症环境以及与神经元突触的直接相互作用 在老年动物中的TBI之后。该提案的初步数据发现，TBI会导致 和CCR 2+巨噬细胞在老化脑中的浸润延长。增加招募外围人员， 衍生的单核细胞显著增加TBI诱导的神经炎性后遗症， 超氧化物生成酶NOX 2的表达增加，这可能会增强损伤诱导的 在老年动物中观察到的认知功能障碍。所有这些发现都表明，在衰老的大脑中， 外周来源的巨噬细胞对TBI相关的炎症反应具有明显的贡献。 基于这些观察，我们假设外周来源的巨噬细胞的强烈浸润 而随之而来的炎症反应是导致认知功能丧失加剧的原因， 降低树突棘密度。在本提案中，我们将确定 巨噬细胞浸润/小胶质细胞活化和损伤后老化脑中的炎症特征。 此外，我们将确定巨噬细胞浸润和树突棘改变之间的机制联系 形态学我们将确定TBI诱导的认知缺陷是否是巨噬细胞诱导的ROS的直接结果 产生和/或不适当的突触修剪。最后，我们将研究是否阻断巨噬细胞 浸润可以减轻损伤诱导的神经毒性，从而减轻认知缺陷。时发现的问题 工作将推进与TBI和测试二相关的二级机制的机械理解 用于治疗TBI诱导的老年人认知缺陷的药物（已经在临床试验中） 动物

Project Summary Traumatic brain injury (TBI) is extremely debilitating for the aging community with both increased incidence and outcome severity within this population. Furthermore, TBI is a strong environmental risk factor for development of Alzheimer's disease and other dementia related illnesses. The importance of age as a prognostic factor after TBI has long been recognized but limited studies have been devoted to understand mechanisms that regulate secondary events that occur after the initial trauma. Even less research has been aimed at studying the mechanisms of cognitive loss in the elderly. The critical changes that affect cognition take place over a long period of time following the initial insult and the innate immune system activation is a key secondary injury mechanism that contributes to chronic neurodegeneration and loss of neurological function. In this proposal we will investigate the respective contribution of infiltrating macrophages and activated resident microglia in production of a neurotoxic and inflammatory milieu as well as direct interactions with neuronal synapses following TBI in an aging animal. Preliminary data for this proposal has found that TBI causes an exacerbated and prolonged CCR2+ macrophage infiltration in the aging brain. The increased recruitment of peripherally derived monocytes significantly augments TBI-induced neuroinflammatory sequelae and is paralleled by an increased expression of the superoxide-generating enzyme NOX2 which may potentiate injury-induced cognitive dysfunction observed in old animals. All together these findings demonstrate that, in the aging brain, peripherally derived macrophages have a distinct contribution to the TBI-related inflammatory response. Based upon these observations we hypothesize that the robust infiltration of peripherally derived macrophages and the consequent inflammatory response is responsible for exacerbated loss of cognitive functions by decreasing dendritic spine density. In this proposal, we will identify the temporal relationships between macrophage infiltration/microglia activation and inflammatory profiles in an aging brain after injury. Furthermore, we will identify mechanistic links between macrophage infiltration and altered dendritic spine morphology. We will determine if TBI-induced cognitive deficits are a direct result of macrophage induced ROS production and/or inappropriate synaptic pruning. Finally, we will investigate if blockade of macrophage infiltration can mitigate injury-induced neurotoxicity thereby alleviating cognitive deficits. Findings from this work will advance mechanistic understanding of secondary mechanisms associated with TBI and test two pharmacological agents (already in clinical trials) for treatment of TBI-induced cognitive deficits in an aging animal.