FSD-C10調(diào)節(jié)阿爾茨海默病雙轉(zhuǎn)基因小鼠炎性微環(huán)境
發(fā)布時間：2018-08-24 12:57
【摘要】：目的:探討新型Rho激酶抑制劑FSD-C10對阿爾茨海默病(Alzheimer disease,AD)模型小鼠腦內(nèi)炎性微環(huán)境的調(diào)節(jié)作用。方法:采用雙轉(zhuǎn)染人β-淀粉樣蛋白前體(β-amyloid protein precursor,APP)695swe基因和人早老素1(presenilin-1,PS1)ΔE9突變基因的8月齡小鼠作為AD動物模型,隨機分為模型組和FSD-C10治療組,分別經(jīng)腹腔注射生理鹽水和FSD-C10(25 mg·kg~(-1)·d~(-1))持續(xù)治療2個月,同月齡野生型小鼠作為正常對照組。應用Morris水迷宮(Morris water maze,MWM)實驗檢測小鼠學習和記憶能力。采用免疫組化和Western blot技術(shù)檢測小鼠腦組織β-淀粉樣蛋白(Aβ)、磷酸化Tau蛋白(p-Tau)、β位點APP剪切酶(BACE)、Toll樣受體4(TLR-4)、磷酸化核因子κB(p-NF-κB)、誘導型一氧化氮合酶(i NOS)和精氨酸酶1(Arg-1)的表達。結(jié)果:與模型組相比,FSD-C10干預能顯著改善APP/PS1雙轉(zhuǎn)基因小鼠學習和記憶能力,減少海馬區(qū)Aβ1-42、p-Tau和BACE的表達,抑制腦內(nèi)炎癥信號通路TLRs/NF-κB軸TLR-4的表達和p-NF-κB的激活,減少i NOS的表達,增加Arg-1的表達。結(jié)論:FSD-C10干預能明顯改善APP/PS1雙轉(zhuǎn)基因小鼠的學習和記憶能力,其機制可能是通過抑制TLRs/NF-κB信號通路激活,減少炎癥因子的分泌及促進M1型炎性小膠質(zhì)細胞向M2型抗炎小膠質(zhì)細胞轉(zhuǎn)化,從而改善APP/PS1雙轉(zhuǎn)基因小鼠腦組織炎癥微環(huán)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.
【作者單位】： 大同大學腦科學研究所;山西中醫(yī)學院"2011"協(xié)同創(chuàng)新中心/神經(jīng)生物學研究中心;復旦大學華山醫(yī)院神經(jīng)病學研究所;
【基金】：國家自然科學基金資助項目(No.81471412;No.81272163) 山西省國際科技合作項目(No.2013081058) 山西中醫(yī)學院“2011”培育計劃項目(No.2011PY-1) 大同市科技局基礎研究計劃項目(No.2017136;No.2014105-1) 大同大學�？蒲许椖�(No.2016K10)
【分類號】：R749.16
[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.
【作者單位】： 大同大學腦科學研究所;山西中醫(yī)學院"2011"協(xié)同創(chuàng)新中心/神經(jīng)生物學研究中心;復旦大學華山醫(yī)院神經(jīng)病學研究所;
【基金】：國家自然科學基金資助項目(No.81471412;No.81272163) 山西省國際科技合作項目(No.2013081058) 山西中醫(yī)學院“2011”培育計劃項目(No.2011PY-1) 大同市科技局基礎研究計劃項目(No.2017136;No.2014105-1) 大同大學�？蒲许椖�(No.2016K10)
【分類號】：R749.16
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