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衰老和阿尔茨海默病期间认知能力下降的发作和进展中的作用。记忆力受损是认知能力下降的早期指标，是由于与氧化还原介导的N-甲基-D-天冬氨酸受体（NMDAR）功能减退相关的突触功能受损。该机制涉及活性氧（ROS），可能来自活化的小胶质细胞，提供了炎症和记忆受损之间的潜在联系。目的1将检验以下假设：认知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功能减退。研究对不同的认知过程采用敏感的行为测试，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、神经胶质细胞活化、氧化应激和NMDAR功能的氧化还原调节的测量相关。我们预测血清中的炎症标志物可预测记忆缺陷的出现，并且对于特定的神经系统，炎症标志物和受损的NMDAR功能可诊断不同的认知障碍表型。 有证据表明，NMDAR突触活性下降会导致转录变化，类似于与年龄相关的认知能力下降和阿尔茨海默病相关的转录变化，这表明慢性炎症导致NMDAR突触活性下降会改变神经营养、神经保护和突触特异性基因的转录。目的2：研究慢性低水平全身性炎症引起的脑转录和认知能力下降。已经开发了全身性炎症模型，其涉及白细胞介素-6（IL-6）的肌肉表达，其升高血清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，血清细胞因子的长期（3个月）增加将导致氧化还原介导的NMDAR功能减退和衰老的转录谱。目的3将研究抗氧化酶的区域选择性上调在保护NMDAR功能，促进年轻的转录谱和拯救认知方面具有选择性作用的想法。

 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.