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：
9266701
负责人：
THOMAS C FOSTER
金额：
$ 30.75万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266701
关键词：
Age Age of Onset Age-associated memory impairment Aging Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Apoptotic Biological Brain Brain region Categories Chronic Cognition Cognitive Data Dementia Diagnostic Disease Dose Episodic memory Generations Genes Genetic Transcription Goals Health Hippocampus (Brain)Impaired cognition Impairment In Vitro Inflammation Link Lipopolysaccharides Long-Term Effects Malaise Measures Medial Mediating Memory Memory Loss Memory impairment Microglia Motivation Motor N-Methyl-D-Aspartate Receptors NADP Nerve Degeneration Neurodegenerative Disorders Neurons Oxidation-Reduction Oxidative Stress Performance Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phenotype Prefrontal Cortex Prostaglandin-Endoperoxide Synthase Publishing Rattus Reactive Oxygen Species Regulation Research Role Serum Specificity Synapses Synaptic Receptors Synaptic plasticity System Testing Transcriptional Regulation Water Work age related aged aging brain base behavior measurement behavior test biological adaptation to stress cognitive function cognitive process cognitive testing cytokine early onset episodic memory impairment executive function hippocampal subregions inflammatory marker inhibitor/antagonist middle age motor impairment neural circuit neuroinflammation novel public health relevance receptor function relating to nervous system response senescence stressor synaptic function transcriptome sequencing

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 promoting an early onset memory impairment and progression of cognitive decline during aging. Impaired episodic memory, an early indicator of cognitive decline, is due to a redox-mediated decrease in the function of synaptic NMDA receptors. 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 decrease in NMDAR function. LPS will be used to induce low- grade systemic inflammation. Studies employ sensitive behavioral tests for different cognitive processes, and can detect changes in motor function or motivation. Impaired cognitive function will be associated with measures of serum and local brain cytokines, oxidative stress, and redox regulation of NMDA receptor function. We predict that inflammatory markers in the serum correlated with the emergence of memory decline and that for specific neural systems, inflammation markers and impaired NMDA receptor function is diagnostic of cognitive impairment phenotypes. Aim 2 examines the progression of cognitive decline. Systemic inflammation induces long-term effects on microglia and synaptic function that outlast systemic markers. To examine long-term effects we will characterize cognition, redox regulation of NMDA receptors, and RNA sequencing to obtain a picture of the transcriptional profile associated with chronic inflammation and cognitive impairment. Research indicates that decreased activity of synaptic NMDA receptors results in a transcriptional profile similar to that associated with aging and memory impairment suggesting that a decrease in NMDAR synaptic activity, due to chronic inflammation, alters transcription of neurotrophic, neuroprotective, and synapse specific genes. We predict that long-lasting changes due to inflammation involve a redox-mediated decrease in synaptic NMDAR activity resulting in a senescent transcription, which increases cellular vulnerability to age-related stressors, and decreases connectivity in specific neural circuits. Aim 3 will examine the effect of anti-inflammatory drugs on cognitive and biological changes associated with inflammation.

描述（由申请人提供）：拟议工作的目标是了解慢性炎症在促进衰老过程中早期记忆损伤和认知衰退进展中的作用。情景记忆受损是认知衰退的早期指标。由于氧化还原介导的突触 NMDA 受体功能下降，该机制涉及活性氧 (ROS)，可能来自激活的小胶质细胞，这提供了炎症与记忆受损之间的潜在联系。认知能力下降的发生受到炎症诱导的氧化应激增加的影响，导致氧化还原介导的 NMDAR 功能下降，将用于诱导低度全身炎症研究采用针对不同认知过程的敏感行为测试，并且可以检测运动功能或动机的变化。我们预测血清中的炎症标记物与记忆的出现相关。衰退对于特定的神经系统，炎症标志物和受损的 NMDA 受体功能是认知障碍表型的诊断，目标 2 检查认知衰退的进展，从而对小胶质细胞和突触功能产生长期影响。 -术语影响，我们将描述认知、NMDA 受体的氧化还原调节以及与慢性炎症和认知障碍相关的转录谱的 RNA 测序。研究表明，突触 NMDA 受体的活性降低会导致与衰老和记忆障碍相关的转录谱相似，表明慢性炎症导致的 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，我们预测炎症引起的长期变化涉及氧化还原。介导的突触 NMDAR 活性降低导致转录衰老，从而增加细胞对年龄相关应激源的脆弱性，并降低特定神经回路的连接性。目标 3 将检查抗炎药物对认知的影响。以及与炎症相关的生物变化。