Aging exacerbates trauma-induced immune pathways and neuronal dysfunction

项目摘要 创伤性脑损伤(TBI)对老龄化社区来说是极其虚弱的，发病率和 结果严重程度在这一人群中。此外，TBI是发展的一个强烈的环境风险因素 阿尔茨海默氏症和其他与痴呆症相关的疾病。年龄作为预后因素的重要性 脑损伤早已得到认可，但致力于了解其调控机制的研究有限。 在最初的创伤之后发生的次要事件。更少的研究是为了研究 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 最初的伤害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。在这份提案中，我们 将研究浸润性巨噬细胞和激活的驻留小胶质细胞在 神经毒性和炎症环境的产生以及与神经元突触的直接相互作用 在一只年老的动物身上观察脑外伤。这项提议的初步数据发现，TBI导致了 衰老大鼠脑内CCR2+巨噬细胞浸润时间延长。外围国家招募的人数增加 来源的单核细胞显著增加脑损伤诱导的神经炎性后遗症，并与 超氧化物歧化酶NOX2的表达增加可能增强损伤诱导 在老年动物中观察到的认知障碍。所有这些发现表明，在老化的大脑中， 外周来源的巨噬细胞对颅脑损伤相关的炎症反应有明显的贡献。 基于这些观察，我们假设外周来源的巨噬细胞的强大渗透 随之而来的炎症反应通过以下方式导致认知功能的恶化 树突棘密度降低。在本提案中，我们将确定以下时间关系： 损伤后老化脑内巨噬细胞的浸润/小胶质细胞的激活和炎性变化。 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。我们将确定脑外伤引起的认知障碍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，我们将调查巨噬细胞是否被阻断 渗透可以减轻损伤所致的神经毒性，从而减轻认知障碍。由此得出的结论 这项工作将促进对与TBI和测试2相关的二级机制的机械学理解 治疗脑损伤所致认知功能障碍的药物(已在临床试验中) 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.