Systemic Inflammation and Central Nervous System Dysfunction

描述（由申请人提供）：越来越多的证据表明，老年人的不良健康结果与慢性轻度炎症状态的发展密切相关。在人类中，炎症的循环标志物，包括炎性细胞因子白细胞介素-6（IL-6），与虚弱、肌肉质量和力量损失、残疾和早期死亡以及急性和慢性认知下降、阿尔茨海默病的发展以及药物和应激诱导的谵妄的风险增加相关或预测。IL-6通过经典的Jak/STAT途径激活许多炎症反应，但我们最近发现IL-6通过转录因子NF κ B的非经典激活起作用，诱导神经元表达和NADPH氧化酶（Nox 2）的激活，NADPH氧化酶是一种多聚体酶复合物，首先被描述为中性粒细胞中的呼吸爆发氧化酶。Nox 2被设计为产生大量的活性氧物质（ROS），主要是超氧阴离子。我们进一步表明，Nox 2在衰老大脑的神经元中被诱导和激活，并且Nox 2实际上是老年小鼠神经元和突触超氧化物产生的主要来源。Nox 2的炎症诱导导致海马、皮质和杏仁核中抑制性中间神经元亚群的超氧化物依赖性损失。在啮齿动物、狗和灵长类动物中观察到这些神经元的缺失，并且已经提出这些神经元的缺失是跨认知领域的认知缺陷的基础。我们将测试的假设，年龄相关的增加IL-6，可能介导的炎症细胞因子TNF α或抗炎细胞因子IL-10的损失，诱导神经元Nox 2的表达，Nox 2，反过来，导致持续的缺陷，在抑制性神经回路所需的学习，注意力和记忆编码。将使用老年野生型小鼠和具有改变IL-6表达、信号传导或特定下游靶点的修饰（遗传或药理学）的老年小鼠来检验我们的假设。各种技术，包括活体动物Nox 2活性的荧光成像，EPR，共聚焦成像，免疫荧光，电生理学和大脑区域特异性功能的行为测试（例如空间学习，海马CA 3依赖性过程）将被用来测试我们假设的序列中的每个环节。最后，将进行一系列调节IL-6的药物和免疫疗法的干预性研究，或提出的事件序列，以确定小鼠中与年龄相关的认知缺陷是否得到改善，并进一步测试我们假设的序列。对人类健康的重要性：认知功能的变化是老年人和社会的重要健康问题。炎症通路激活与大脑衰老之间的联系仍有待充分确定。本文提出的研究旨在探索一种可能将炎症途径与年龄相关的认知缺陷联系起来的途径，并有可能为衰老大脑中重要且可能可逆的生物和神经回路变化提供额外的见解。

DESCRIPTION (provided by applicant): Increasing evidence indicates that adverse health outcomes in older adults are strongly associated with the development of a state of chronic, mild inflammation. In humans, circulating markers of inflammation, including the inflammatory cytokine interleukin-6 (IL-6), are associated with, or predict, enhanced risk of frailty, loss of muscle mass and strength, disability, and early mortality, as well as acute and chronic cognitive decline, development of Alzheimer's disease, and drug- and stress-induced delirium. IL-6 activates a host of inflammatory actions through classical Jak/STAT pathway, but we recently found that IL-6, acting through non-cannonical activation of the transcription factor, NFkB, induces neuronal expression and activation of NADPH oxidase (Nox2), a multimeric enzyme complex first described as the respiratory burst oxidase in neutrophils. Nox2 is designed to produce large amounts of reactive oxygen species (ROS), primarily superoxide anion. We have further shown that Nox2 is induced and activated in neurons in the aging brain, and that Nox2 is in fact the major source of neuronal and synaptic superoxide production in aged mice. Inflammatory induction of Nox2 led to a superoxide-dependent loss of subsets of inhibitory interneurons in hippocampus, cortex, and amygdala. Loss of these neurons is observed in rodents, dogs, and primates, and has been proposed to underlie cognitive deficits across cognitive domains. We will test the hypothesis that age-related increase in IL-6, potentially mediated by the inflammatory cytokine TNFa or loss of the anti-inflammatory cytokine IL-10, induces neuronal Nox2 expression and that Nox2, in turn, results in persistent deficits in inhibitory neural circuits required for learning, attention, and memory encoding. Aged wild-type mice, and aged mice with modifications (either genetic or pharmacologic) which modify IL-6 expression, signaling, or specific downstream targets, will be used to test our hypothesis. A variety of techniques, including live animal fluorescence imaging of Nox2 activity, EPR, confocal imaging, immuno-fluorescence, electrophysiology and behavioral testing of brain region-specific function (e.g. spatial learning, a hippocampal CA3-dependent process) will be used to test each link in our hypothesized sequence. Finally, a series of interventional studies with drugs and immunotherapies which modulate IL-6, or the proposed sequence of events, will be carried out to determine whether age-related cognitive deficits in the mice are ameliorated, and to further test our hypothetical sequence. Importance to Human Health: Changes in cognitive function are an important health concern for older adults, and for society. The link between inflammatory pathway activation and aging in the brain remains to be fully defined. The studies proposed here are designed to explore one pathway which may link inflammatory pathways and age-related cognitive deficits, with the potential to provide additional insights into important and possibly reversible biological and neural circuitry changes in the aging brain.