Systemic Inflammation and Central Nervous System Dysfunction

全身炎症和中枢神经系统功能障碍

• 批准号: 8113936
• 负责人: Laura L Dugan
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113936
• 关键词: Acute; Adipocytes; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amygdaloid structure; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Attention; Behavior; Behavioral; Biological; Biology; Brain; Brain region; Canis familiaris; Cell Culture Techniques; Cells; Chronic; Chronic Disease; Cognitive; Cognitive deficits; Collaborations; Complex; Delirium; Development; Disease; Elderly; Electron Spin Resonance Spectroscopy; Electrophysiology (science); Emotional; Etiology; Event; Fluorescence; Functional disorder; Genetic; Genetic Variation; Health; Hippocampus (Brain); Hormones; Human; Hydrogen Peroxide; Image; Immunotherapy; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-10; Interleukin-6; Interneurons; Intervention; Ion Channel; Learning; Life; Link; Mediating; Mediator of activation protein; Memory; Microglia; Modeling; Modification; Molecular; Multienzyme Complexes; Mus; Muscle; NADPH Oxidase; Neuraxis; Neurons; Neurotransmitter Receptor; Nuclear; Operative Surgical Procedures; Outcome; Outcome Measure; Oxidants; Oxidation-Reduction; Parvalbumins; Pathway interactions; Performance; Pharmaceutical Preparations; Phenotype; Physiological; Plasma; Primates; Process; Production; Protein Isoforms; Reactive Oxygen Species; Reporting; Risk; Rodent; Role; Series; Signal Transduction; Slice; Societies; Source; Stress; Superoxides; Synapses; TNF gene; Techniques; Testing; Treatment Efficacy; Wild Type Mouse; age related; aged; aging brain; behavior test; cell type; cognitive change; cognitive function; conditioned fear; cytokine; design; disability; fluorescence imaging; frailty; human CYBA protein; in vivo; inflammatory marker; information processing; inhibitory neuron; insight; memory encoding; middle age; mortality; mouse model; muscle form; muscle strength; neural circuit; neuron loss; neutrophil; prevent; protein expression; public health relevance; senescence; stressor; superoxide-generating NADPH oxidase; transcription factor

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. PUBLIC HEALTH RELEVANCE: Older adults are more vulnerable to the development of adverse cognitive outcomes, including decline in cognitive function and the development of delirium, after acute illness, surgery, and other stressors. The exact etiology and molecular mechanisms are not known, but recent studies suggest a role for the pro- inflammatory cytokine interleukin-6 (IL-6) in many aging-related disorders, including cognitive vulnerability. Our project seeks to determine the mechanisms which underlie the association between systemic inflammation, IL-6, and cognitive vulnerability, and to try to determine whether interventions which target IL-6 or downstream pathways might prevent age-related cognitive decline.

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，包括炎症细胞因子白细胞介素-6（IL-6）在内的循环标记与较弱的风险，肌肉质量和力量，残疾和早期死亡以及急性有关以及慢性认知能力下降，阿尔茨海默氏病的发展以及药物和压力引起的del妄。 IL-6通过经典的JAK/STAT途径激活了许多炎症作用，但是我们最近发现，通过转录因子的非通道激活NFKB起作用的IL-6会诱导NADPH氧化酶（NOX2），，，诱导神经元表达和激活。首先被描述为中性粒细胞中的呼吸爆发氧化酶的多聚酶复合物。 NOX2旨在产生大量的活性氧（ROS），主要是超氧化物阴离子。我们进一步表明，NOX2在衰老大脑的神经元中诱导和激活，而NOX2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。 NOX2的炎症诱导导致海马，皮质和杏仁核中抑制性中间神经元子集的超氧化物依赖性丧失。在啮齿动物，狗和灵长类动物中观察到这些神经元的丧失，并已提出在认知领域的认知缺陷构成的基础。我们将检验以下假设：IL-6与年龄相关的增加，可能是由炎症性细胞因子TNFA介导的或抗炎细胞因子IL-10的丧失，诱导NOX2表达，而NOX2则又导致了NOX2，而NOX2则导致持续的缺陷。学习，注意力和记忆编码所需的抑制神经回路。老化的野生型小鼠和具有修饰的老年小鼠（遗传学或药物），可修改IL-6表达，信号传导或特定的下游靶标，用于检验我们的假设。多种技术，包括NOX2活性的活动物荧光成像，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CA3依赖性过程）可用于测试我们假设的序列中的每个链接。最后，将对调节IL-6的药物和免疫疗法的一系列介入研究，或将提出的事件序列进行，以确定小鼠中与年龄相关的认知缺陷是否得到改善，并进一步测试我们的假设序列。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。炎症途径激活与大脑衰老之间的联系尚待充分定义。此处提出的研究旨在探索一种途径，该途径可能会将炎症途径和与年龄有关的认知缺陷联系起来，并有可能提供对衰老大脑中重要且可能可逆的生物学和神经电路变化的更多见解。 公共卫生相关性：老年人更容易受到不利认知结果的发展，包括认知功能的下降和del妄的发展，急性疾病，手术和其他压力源。确切的病因和分子机制尚不清楚，但最近的研究表明，在许多与衰老有关的疾病（包括认知脆弱性）中，炎性细胞因子白细胞介素6（IL-6）的作用。我们的项目旨在确定系统性炎症，IL-6和认知脆弱性之间关联的机制，并尝试确定针对IL-6或下游途径的干预措施是否可能阻止与年龄相关的认知能力下降。