Systemic inflammation in regulating the onset and progression of brain aging

 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早发性记忆损害和衰老过程中认知能力下降的进展中所起的作用。情景记忆受损是认知衰退的早期指标，是由于氧化还原介导的突触NMDA受体功能下降所致。其机制涉及活性氧物种(ROS)，可能来自激活的小胶质细胞，在炎症和记忆受损的出现之间提供了潜在的联系。目的1验证一种假说，即炎症导致氧化应激增加，导致NMDAR功能下降，从而影响认知功能下降的发生。脂多糖将被用来诱导低度全身炎症。研究使用针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、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减退的出现相关，对于特定的神经系统，炎症标志物和NMDA受体功能受损是认知障碍表型的诊断。目标2研究认知能力下降的进程。全身性炎症对小胶质细胞和突触功能的长期影响比全身性标记物持续时间更长。为了检验长期影响，我们将表征认知、NMDA受体的氧化还原调节和RNA测序，以获得与慢性炎症和认知障碍相关的转录图谱。研究表明，突触NMDA受体活性的降低导致了类似于衰老和记忆损伤的转录模式，这表明由于慢性炎症，NMDAR突触活性的降低改变了神经营养、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活性下降，导致转录衰老，这增加了细胞对年龄相关应激源的脆弱性，并降低了特定神经回路的连通性。目的3将研究抗炎药物对与炎症相关的认知和生物变化的影响。

 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.