γ-氨基丁酸经CP-CEBPα-miR-34a抑制HDAC2/3下调炎性因子表达阻遏AD发生发展的作用机制

Alzheimer's disease (AD) is one of the prominent problems faced by the aging society. Inflammatory response is closely related to the occurrence and development of AD. γ-aminobutyric acid (GABA), an inhibitory neurotransmitter and functional food factor, has been reported to decrease in AD brain and may regulate inflammatory responses by reducing the expression of inflammatory factors IL-1β, IL-6 and TNFα in microglia cells and astrocytes. Studies have shown that IL-1β, IL-6 and TNFα are also regulated by HDACs, and HDAC2/3 is closely related to AD. We found that GABA inhibited HDAC2/3 expression through non-receptor pathway, suggesting that GABA may regulate the expression of inflammatory factors through HDAC2/3. Bioinformatics predicted that miR-34a might regulate HDAC2/3, while CEBPα could regulate miR-34a. GABA reduces creatine phosphate (CP) level, which can inhibit CEBP homologous protein expression. Therefore, this project intends to use in vivo and in vitro experiments to prove that GABA inhibits HDAC2/3 expression through CP-CEBPα-miR-34a pathway, so as to down-regulate the expression of IL-1β, IL-6 and TNFα against the occurrence and development of AD. The study may provide new clues to elucidate the pathogenesis of AD and explore the effective prevention and treatment of AD.

阿尔茨海默病（AD）是社会老龄化所面临的突出问题之一，炎性反应与AD发生发展密切相关。功能食品因子γ-氨基丁酸（GABA）是一种抑制性神经递质，其在AD脑中含量降低，并可能通过抑制小胶质细胞和星形胶质细胞炎性因子IL-1β、IL-6及TNFα表达调控炎性反应，但机制尚不明确。研究显示炎性因子可被组蛋白去乙酰化酶（HDACs）调控，而HDAC2/3与AD关系密切。我们发现GABA通过非受体途径抑制HDAC2/3，提示GABA可能通过HDAC2/3调控炎性因子表达。生物信息学预测miR-34a可调控HDAC2/3，CEBPα能调控miR-34a。GABA降低磷酸肌酸（CP）水平，而CP可能抑制CEBPα表达。因此，本项目拟利用体内外实验，证明GABA通过CP-CEBPα-miR-34a抑制HDAC2/3，下调炎性因子表达，拮抗AD发生发展。研究可为阐释AD发病机制、探索AD有效防治提供新线索。

阿尔茨海默病（AD）是社会老龄化所面临的不可回避的突出问题之一，揭示AD的发病机制寻找有效的防治手段已迫在眉睫。炎性反应是AD发生发展的中心环节，γ-氨基丁酸（GABA）在AD脑组织中的含量异常降低，并可能通过减少星形胶质细胞致炎因子白细胞介素-1β（IL-1β）、IL-6、肿瘤坏死因子α（TNFα）表达调节炎性反应，因此GABA在AD脑中的炎性反应中发挥至关重要的作用。本项目以GABA通过非受体途径抑制组蛋白去乙酰化酶（HDACs）表达为切入点，探讨了GABA抑制HDAC2/3表达的作用机制以及HDAC2/3介导GABA下调星形胶质细胞致炎因子拮抗AD发生发展的作用机制。研究结果显示在U251细胞中miR-34a模拟物和抑制剂可分别抑制和上调HDAC2/3表达，并且miR-34a可以和HDAC2结合直接抑制其表达；沉默CCAAT增强子结合蛋白α（CEBPα）可下调miR-34a和HDAC2/3表达；磷酸肌酸（CP）可升高CEBPα和miR-34a表达，抑制HDAC2/3表达。进一步研究结果显示GABA可拮抗Aβ诱导的U251细胞IL-1β、IL-6、TNFα和HDAC2/3表达的升高以及CP水平、CEBPα和miR-34a表达的降低；沉默HDAC2/3可降低IL-1β、IL-6及TNFα的表达。同时动物实验结果显示GABA可以改善AD模型小鼠认知功能障碍并减少大脑皮质Aβ沉积；GABA抑制AD模型小鼠大脑皮质IL-1β、IL-6、TNFα和HDAC2/3表达的升高以及CP水平、CEBPα及miR-34a表达的降低。综上，研究结果证明了GABA通过CP-CEBPα-miR-34a抑制HDAC2/3表达，从而下调星形胶质细胞致炎因子表达，进而拮抗AD发生发展。本项目的研究结果可为延缓AD发生发展提供新的理论依据和潜在防治靶点，以期促使基础研究成果走向应用。

内容获取失败，请点击重试