FSD-C10调节阿尔茨海默病双转基因小鼠炎性微环境

发布时间：2018-08-24 12:57

【摘要】：目的:探讨新型Rho激酶抑制剂FSD-C10对阿尔茨海默病(Alzheimer disease,AD)模型小鼠脑内炎性微环境的调节作用。方法:采用双转染人β-淀粉样蛋白前体(β-amyloid protein precursor,APP)695swe基因和人早老素1(presenilin-1,PS1)ΔE9突变基因的8月龄小鼠作为AD动物模型,随机分为模型组和FSD-C10治疗组,分别经腹腔注射生理盐水和FSD-C10(25 mg·kg~(-1)·d~(-1))持续治疗2个月,同月龄野生型小鼠作为正常对照组。应用Morris水迷宫(Morris water maze,MWM)实验检测小鼠学习和记忆能力。采用免疫组化和Western blot技术检测小鼠脑组织β-淀粉样蛋白(Aβ)、磷酸化Tau蛋白(p-Tau)、β位点APP剪切酶(BACE)、Toll样受体4(TLR-4)、磷酸化核因子κB(p-NF-κB)、诱导型一氧化氮合酶(i NOS)和精氨酸酶1(Arg-1)的表达。结果:与模型组相比,FSD-C10干预能显著改善APP/PS1双转基因小鼠学习和记忆能力,减少海马区Aβ1-42、p-Tau和BACE的表达,抑制脑内炎症信号通路TLRs/NF-κB轴TLR-4的表达和p-NF-κB的激活,减少i NOS的表达,增加Arg-1的表达。结论:FSD-C10干预能明显改善APP/PS1双转基因小鼠的学习和记忆能力,其机制可能是通过抑制TLRs/NF-κB信号通路激活,减少炎症因子的分泌及促进M1型炎性小胶质细胞向M2型抗炎小胶质细胞转化,从而改善APP/PS1双转基因小鼠脑组织炎症微环境。
[Abstract]:Aim: to investigate the effects of FSD-C10, a novel inhibitor of Rho kinase, on inflammatory microenvironment in brain of Alzheimer's disease (Alzheimer disease,AD) mice. Methods: the 8-month-old mice with double transfection of human 尾 -amyloid protein precursor,APP 695swe gene and presenilin-1,PS1 螖 E9 mutation gene were used as AD animal models. The mice were randomly divided into two groups: model group and FSD-C10 treatment group. Normal saline and FSD-C10 (25 mg kg~ (-1) d ~ (-1) were injected intraperitoneally for 2 months, and wild-type mice of the same age served as normal control group. The learning and memory abilities of mice were measured by Morris water maze (Morris water maze,MWM. The expressions of 尾 -amyloid protein (A 尾), phosphorylated Tau protein (p-Tau), 尾 -site APP shearing enzyme (BACE) Toll-like receptor 4 (TLR-4), phosphorylated nuclear factor- 魏 B (p-NF- 魏 B), inducible nitric oxide synthase (i NOS) and arginase 1 (Arg-1) were detected by immunohistochemical and Western blot techniques. Results: compared with the model group, the intervention of FSD-C10 significantly improved the learning and memory ability of APP/PS1 transgenic mice, reduced the expression of A 尾 1-42 p-Tau and BACE in hippocampus, inhibited the expression of TLRs/NF- 魏 B axis TLR-4 and p-NF- 魏 B, and reduced the expression of I NOS. Increase the expression of Arg-1. Conclusion the intervention of FSD-C10 can significantly improve the ability of learning and memory in APP/PS1 transgenic mice, and its mechanism may be by inhibiting the activation of TLRs/NF- 魏 B signaling pathway. To reduce the secretion of inflammatory factors and to promote the transformation of M1 type inflammatory microglia into M2 anti-inflammatory microglia, thus improving the inflammatory microenvironment of brain tissue of APP/PS1 double transgenic mice.
【作者单位】：大同大学脑科学研究所;山西中医学院"2011"协同创新中心/神经生物学研究中心;复旦大学华山医院神经病学研究所;
【基金】：国家自然科学基金资助项目(No.81471412;No.81272163) 山西省国际科技合作项目(No.2013081058) 山西中医学院“2011”培育计划项目(No.2011PY-1) 大同市科技局基础研究计划项目(No.2017136;No.2014105-1) 大同大学校科研项目(No.2016K10)
【分类号】：R749.16

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