Systemic inflammation in regulating the onset and progression of brain aging

全身炎症调节大脑衰老的发生和进展

基本信息

批准号：
9915827
负责人：
THOMAS C FOSTER
金额：
$ 37.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915827
关键词：
Age Age-associated memory impairment Aging Alzheimer&apos s Disease Animals Anti-Inflammatory Agents Antiinflammatory Effect Antioxidants Apoptotic Behavior Behavioral Brain Brain region Cells Chronic Cognition Cognitive aging Data Dementia Development Diagnostic Encephalitis Executive Dysfunction Female Gene Expression Genes Genetic Transcription Goals Health Immune Impaired cognition Impairment In Vitro Inflammation Injections Interleukin-6 Intramuscular Injections Link Lipopolysaccharides Measures Medial Mediating Memory Memory impairment Methods Microglia Modeling Motivation Motor Muscle N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurons Oxidation-Reduction Oxidative Stress Performance Peripheral Pharmaceutical Preparations Phenotype Prefrontal Cortex Publishing Rattus Reaction Time Reactive Oxygen Species Regulation Role Serum Sex Differences Specificity Stress Synapses Synaptic Receptors Synaptic plasticity System Testing Up-Regulation Viral Viral Vector Virus Work age related age related neurodegeneration aged aging brain antioxidant enzyme astrogliosis base behavior measurement behavior test biological adaptation to stress cell type cognitive function cognitive process cytokine executive function glial activation inflammatory marker male middle age motor impairment next generation sequencing novel preservation public health relevance receptor function relating to nervous system selective expression senescence stressor synaptic function vigilance

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed work is to provide an understanding the role of chronic inflammation in the onset and progression of cognitive decline during aging and Alzheimer's disease. Impaired memory, an early indicator of cognitive decline, is due to impaired synaptic function associated with a redox-mediated hypofunction of N-methyl-D-aspartate receptors (NMDARs). The mechanism involves reactive oxygen species (ROS), possibly from activated microglia, providing a potential link between inflammation and the emergence of impaired memory. Aim 1 will test the hypothesis that the onset of cognitive decline is influenced by an inflammation induced increase in oxidative stress, resulting in a redox-mediated NMDAR hypofunction. Studies employ sensitive behavioral tests for different cognitive processes, and can detect changes in motor function or motivation. Impaired cognitive function will be related to measures of serum and local brain cytokines, glial activation, oxidativ stress, and redox regulation of NMDAR function. We predict that inflammatory markers in the serum are predictive of the emergence of memory deficits and that for specific neural systems, inflammation markers, and impaired NMDAR function is diagnostic of different cognitive impairment phenotypes. Evidence indicates that decreased NMDAR synaptic activity results in transcriptional changes similar to that associated with age-related cognitive decline and Alzheimer's disease suggesting that a decrease in NMDAR synaptic activity, due to chronic inflammation, alters transcription of neurotrophic, neuroprotective, and synapse specific genes. Aim 2 examines brain transcription and cognitive decline due to chronic low-level of systemic inflammation. A systemic inflammation model has been developed and involves muscle expression of interleukin-6 (IL-6), which elevates serum IL-6 and induces brain astrogliosis and microglia activation. We predict that a long-term (3 months) increase in serum cytokines will result in a redox-mediated NMDAR hypofunction and a senescent transcription profile. Aim 3 will examine the idea that region selective upregulation of antioxidant enzymes will have a selective effect in protecting NMDAR function, promoting a youthful transcriptional profile, and rescuing cognition.

描述（由申请人提供）：拟议工作的目标是了解慢性炎症在衰老和阿尔茨海默氏病期间认知衰退的发生和进展中的作用。记忆受损是认知衰退的早期指标。突触功能与氧化还原介导的 N-甲基-D-天冬氨酸受体 (NMDAR) 功能减退相关，该机制涉及活性氧 (ROS)，可能来自激活的小胶质细胞，在炎症和出现之间提供了潜在的联系。目标 1 将检验认知衰退的发生受到炎症诱导的氧化应激增加的影响，从而导致氧化还原介导的 NMDAR 功能减退。研究采用针对不同认知过程的敏感行为测试，并可以检测变化。认知功能受损与血清和局部脑细胞因子、神经胶质活化、氧化应激和 NMDAR 功能的氧化还原调节的测量有关，我们预测血清中的炎症标志物可预测其出现。记忆缺陷以及特定神经系统、炎症标志物和 NMDAR 功能受损可以诊断不同的认知障碍表型。有证据表明，NMDAR 突触活性降低会导致转录变化，类似于与年龄相关的认知衰退和阿尔茨海默病相关的转录变化。慢性炎症导致的 NMDAR 突触活性降低会改变神经营养、神经保护和突触特异性基因的转录。目标 2 检查由于慢性低水平全身炎症导致的大脑转录和认知能力下降。已经开发出一种全身炎症模型，涉及白细胞介素 6 (IL-6) 的肌肉表达，该模型会升高血清 IL-6 并诱导脑星形胶质细胞增生和小胶质细胞活化，我们预测血清细胞因子会长期（3 个月）增加。将导致氧化还原介导的 NMDAR 功能减退和衰老转录谱。目标 3 将检验抗氧化酶的区域选择性上调将在保护 NMDAR 功能、促进年轻转录谱等方面具有选择性作用的想法。拯救认知。