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

• 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
• 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

 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（由适用提供）：拟议工作的目的是提供理解慢性感染在促进衰老期间认知能力下降的早期发作记忆障碍和进展中的作用。发作记忆受损，是认知能力下降的早期指标，是由于氧化还原介导的突触NMDA受体功能的下降所致。该机制涉及活化的小胶质细胞可能的活性氧（ROS），从而提供了炎症与记忆受损的出现之间的潜在联系。 AIM 1将检验以下假设：认知下降的发作受注射诱导的氧化物胁迫增加的影响，从而导致氧化还原介导的NMDAR功能降低。 LPS将用于诱导低级全身炎症。研究员工对不同认知过程的敏感行为测试，并可以检测运动功能或动机的变化。认知功能受损将与血清和局部脑细胞因子的测量，氧化应激以及NMDA受体功能的氧化还原调节有关。我们预测，血清中的炎症标志物与记忆下降的出现相关，并且对于特定的神经元系统，感染标记和NMDA受体功能受损是认知障碍表型的诊断。 AIM 2考试认知能力下降的进展。全身性炎症会影响对小胶质细胞和突触功能的长期影响，使全身标记物。为了检查长期效应，我们将表征认知，NMDA受体的氧化还原调节以及RNA测序，以获得与慢性炎症和认知障碍有关的转录特征的图片。研究表明，突触NMDA受体的活性降低会导致转录谱类似于与衰老和记忆障碍相关的转录谱，这表明NMDAR突触活性降低，由于慢性感染，改变了神经营养性，神经保护性和突触特有基因的转录。我们预测，由于感染引起的持久变化涉及突触NMDAR活性的氧化还原介导的降低，从而导致感觉转录，从而增加了与年龄相关的压力源的细胞脆弱性，并降低了特定神经电路的连通性。 AIM 3将检查抗炎药对与炎症相关的认知和生物学变化的影响。