Neuroinflammation and behavior in the aged

项目摘要 在衰老的大脑中，小胶质细胞表现出更加活化的表型，并且对 从免疫到大脑的信号通路中产生的信息。因此，在感染的老年人中， 小胶质细胞对来自外周免疫系统的信号反应过度，并产生过量的前- 炎性细胞因子导致行为病理学，包括严重的认知缺陷。在几个 在神经退行性疾病中，小胶质细胞活化与细胞内活性氧物质有关， 充当第二信使并刺激氧化还原敏感性转录因子（例如，NF B和AP-1）， 控制促炎基因。因此，调节小胶质细胞中的氧化应激是一种潜在的 治疗方法，不仅减少与年龄相关的氧化损伤，而且表达的前- 炎症基因，这已被证明是随着年龄的增长而增加。为此，建议的目标 一项研究是调查小胶质细胞中抗氧化反应途径的激活是否会减少 在衰老的大脑神经炎症，并防止过度生产的促炎细胞因子 在感染期间。具体的假设是，功能失调的核因子E2相关因子2（Nrf 2）信号传导 负责衰老大脑中小胶质细胞引发和基底炎症增加， 用异硫氰酸酯萝卜硫素（SFN）-十字花科植物中天然存在的化合物激活Nrf 2 蔬菜-将防止有害的夸张的神经炎症反应和由此产生的行为 外周感染时的病理学。研究计划首先评估Nrf 2信号，抗氧化剂， 反应元件（ARE）靶基因，氧化应激和炎症在老年小鼠的大脑中， 小胶质细胞分离自老年小鼠。随后的研究将确定使用SFN激活Nrf 2是否会降低基础 脑中的氧化应激和炎症水平以及小胶质细胞对来自脑内的信号的反应性， 感染期间的外周免疫系统。最后，我们将确定激活Nrf 2是否能保护老年小鼠， 对抗感染相关的行为病理学和神经元损伤。这项研究将是第一个确定是否 Nrf 2-ARE信号传导功能障碍是小胶质细胞引发和基底炎症增加的原因。 衰老的大脑，如果激活Nrf 2-ARE通路， 外周感染时的神经炎症反应和由此产生的行为病理学。

PROJECT SUMMARY In the senescent brain, microglial cells display a more activated phenotype and are hypersensitive to messages emerging from immune-to-brain signaling pathways. Thus, in old individuals with an infection, microglia over react to signals from the peripheral immune system and produce excessive levels of pro- inflammatory cytokines causing behavioral pathology including serious deficits in cognition. In several neurodegenerative diseases, microglial activation has been linked to intracellular reactive oxygen species that act as second messengers and stimulate redox-sensitive transcription factors (e.g., NF¿B and AP-1) that control pro-inflammatory genes. Thus, regulating oxidative stress in microglia represents a potential therapeutic approach to not only reducing age-related oxidative damage but also the expression of pro- inflammatory genes, which has been shown to increase with age. To this end, the goal of the proposed research is to investigate if activation of the antioxidant response pathway in microglia reduces neuroinflammation in the senescent brain and prevents excessive production of pro-inflammatory cytokines during infection. The specific hypothesis is that dysfunctional Nuclear factor E2-related factor 2 (Nrf2) signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and that activation of Nrf2 with isothiocyanate sulforaphane (SFN)-a naturally occurring compound in cruciferous vegetables-will prevent the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection. The research plan begins by assessing Nrf2 signaling, antioxidant response element (ARE) target genes, oxidative stress and inflammation in the brain of old mice and in microglia isolated from old mice. Subsequent studies will determine if activating Nrf2 with SFN reduces basal levels of oxidative stress and inflammation in brain as well as the reactivity of microglia to signals from the peripheral immune system during infection. Finally, we will determine if activating Nrf2 protects old mice against infection-related behavioral pathology and neuronal injury. This study will be the first to determine if dysfunctional Nrf2-ARE signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and if activation of the Nrf2-ARE pathway prevents the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection.