Aging Oxidative Stress and Microglia

描述(由申请人提供)： 问题陈述：近年来，大量证据表明，炎症在衰老过程中在大脑中发展，可能是中枢神经系统突触可塑性下降和神经退行性疾病发展的潜在因素。然而，特定脑部炎症反应的原因和后果仍然不是很清楚。我们发现，通过各种治疗改善脑部炎症对突触可塑性受损的几个指标有有益的作用。然而，似乎炎症过程变得越先进，就越难逆转其影响。这一建议旨在针对激活大脑炎症通路的早期调节失调事件，以验证通过早期干预炎症可以在衰老期间保护学习的假设。在目前的资助期，我们已经证明了通过注入TNF1在小脑中诱导炎症破坏了年轻大鼠的小脑突触可塑性(运动学习)，而阻断老年大鼠的TNF1则适度地改善了运动学习。小胶质细胞是脑内活性氧簇(ROS)的重要来源，也是其他炎症信号的重要来源，如TNF1等促炎细胞因子，因此可能在调节中枢神经系统氧化应激和神经退行性疾病中发挥作用。我们最近的证据表明，在衰老的大脑中，神经元和小胶质细胞之间通讯的关键调节因子被破坏，这可能是观察到的TNF1增加和慢性炎症状态之前和开始的因素之一。作为这个正在进行的项目的一部分，我们计划调查这些神经元-神经胶质通讯调节器的作用。这些研究的一个主要焦点是检验这一假说，即神经元-胶质细胞通讯的关键调节器的中断将导致衰老表型。我们将研究两种可能的神经元和神经胶质细胞之间的通讯调节因子，Fractalkine和CD200。第二个目的是研究这样一种假设，即老年大脑中关键调节器的替换将恢复年轻的表型。为了研究这个问题，我们将向老年大鼠的小脑中注射Fractalkine(一种抗炎趋化因子)或CD200(一种抗炎免疫球蛋白)，并对它们在小脑学习任务中的表现进行测试，我们已经证明该任务对炎症变化敏感，延迟眨眼条件。第三个目的是检验这样一种假设，即老年大脑中关键调节器的替换将恢复年轻的表型。我们将向海马区注入Fractalkine或CD200，并检查认知功能和LTP作为海马区突触可塑性的指标。 公共卫生相关性： 近年来，广泛的证据表明，炎症在衰老过程中在大脑中发展，可能是中枢神经系统突触可塑性下降和神经退行性疾病发生的潜在因素。然而，特定脑部炎症反应的原因和后果仍然不是很清楚。我们发现，通过各种治疗改善脑部炎症对突触可塑性受损的几个指标有有益的作用。然而，似乎炎症过程变得越先进，就越难逆转其影响。这一建议旨在针对激活大脑炎症通路的早期调节失调事件，以验证通过早期干预炎症可以在衰老期间保护学习的假设。这将使我们了解针对新干预措施发展的关键途径，以改善认知老化。

DESCRIPTION (provided by applicant): Statement of the Problem: In recent years, extensive evidence has shown that inflammation develops in the brain during aging and may be the underlying factor for the development of declines in synaptic plasticity in the CNS and neurodegenerative disease. However, the causes and consequences of specific brain inflammatory responses are still not well understood. We have found that amelioration of brain inflammation with various treatments has beneficial actions on several indicators of impaired synaptic plasticity. However, it appears that the more advanced the inflammatory process becomes, the more difficult it is to reverse its effects. This proposal is aimed at targeting early dysregulating events that activate brain inflammatory pathways to test the hypothesis that learning can be protected during aging by early intervention against inflammation. In the current funding period we have demonstrated that inducing inflammation in the cerebellum by infusing TNF1 disrupts cerebellar synaptic plasticity (motor learning) in young rats while blocking TNF1 in aged rats modestly improves motor learning. Microglial cells are an important source of reactive oxygen species (ROS) in the brain as well as other inflammatory signals such as pro-inflammatory cytokines such as TNF1 and therefore may play a role in modulating CNS oxidative stress and neurodegenerative diseases. We have recent evidence that key regulators of communication between neurons and microglia are disrupted in the aged brain and may be one of the factors that precedes and initiates the observed increase in TNF1 and a chronic inflammatory state. We plan to investigate the role of these neuronal-glial communication regulators as part of this ongoing project. A major focus of these studies is to examine the hypothesis that disruption of key modulators of neuronal-glial communication will lead to an aging phenotype. We will examine two possible regulators of communication between neurons and glia, fractalkine and CD200. The second aim is to investigate the hypothesis that replacement of key modulators in the aged brain will re-instate a young phenotype. To examine this question we will administer fractalkine (an anti-inflammatory chemokine) or CD200 (an anti-inflammatory immunoglobulin) into the cerebellum of aged rats and they will be tested for performance on a cerebellar learning task that we have demonstrated is sensitive to changes in inflammation, delay eyeblink conditioning. The third aim examines the hypothesis that replacement of key modulators in the aged brain will re-instate a young phenotype. We will administer fractalkine or CD200 into the hippocampus and examines cognitive function and LTP as indexes of synaptic plasticity in the hippocampus. PUBLIC HEALTH RELEVANCE: In recent years, extensive evidence has shown that inflammation develops in the brain during aging and may be the underlying factor for the development of declines in synaptic plasticity in the CNS and neurodegenerative disease. However, the causes and consequences of specific brain inflammatory responses are still not well understood. We have found that amelioration of brain inflammation with various treatments has beneficial actions on several indicators of impaired synaptic plasticity. However, it appears that the more advanced the inflammatory process become, the more difficult it is to reverse its effects. This proposal is aimed at targeting early dysregulating events that activate brain inflammatory pathways to test the hypothesis that learning can be protected during aging by early intervention against inflammation. This will inform us as to critical pathways to target for the development of new interventions to improve cognitive aging.