IL-33对阿尔茨海默病模型大鼠脑组织内β-淀粉样蛋白的清除作用及其机制
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摘要
目的:探讨白细胞介素33(IL-33)对阿尔茨海默病(AD)模型大鼠学习记忆能力和脑组织内β-淀粉样蛋白(Aβ)和Ⅱ型辅助性T细胞(Th2)水平的影响,阐明IL-33对AD模型大鼠脑组织内Aβ的清除作用及其机制。方法:70只雄性SD大鼠随机分为正常对照组(皮下注射生理盐水,灌胃双蒸水),模型组,假手术组,极低、低、中和高剂量IL-33组(0.01、0.10、1.00和10.00mg·L~(-1)),每组10只。除正常对照组外,其余各组大鼠皮下注射D-半乳糖和灌胃AlCl3,每日1次,连续60d。末次给药后,进行大鼠跳台实验和Morris水迷宫实验,观察大鼠的潜伏期、错误次数、逃避潜伏期、目标象限停留时间和游泳距离。行为学检测结束后,IL-33各剂量组大鼠侧脑室注射相应剂量IL-33,假手术组大鼠侧脑室注射生理盐水。采用ELISA法检测各组大鼠脑组织内Aβ和Th2水平。结果:跳台实验,与正常对照组比较,模型组大鼠的错误次数增多(t=8.154,P<0.01),潜伏期明显缩短(t=4.579,P<0.01);Morris水迷宫实验,与正常对照组比较,模型组大鼠逃避潜伏期明显延长(t=27.810,P<0.01),在目标象限内滞留时间和游泳距离明显缩短(t=3.767,P<0.01;t=1.973,P<0.05)。ELISA法检测,模型组大鼠脑组织中Aβ水平较正常对照组明显升高(t=3.222,P<0.05),低、中和高剂量IL-33组大鼠脑组织内Aβ水平较模型组明显降低(P<0.05);模型组大鼠脑组织内Th2水平较正常对照组明显降低(t=4.646,P<0.01),低、中和高剂量IL-33组大鼠脑组织内Th2水平较模型组明显升高(P<0.05)。结论:IL-33对AD模型大鼠脑组织内Aβ有清除作用,其作用机制可能与提高大鼠脑组织内Th2水平有关。
Objective:To explore the influence of interleukin-33(IL-33)on the abilities of spatial learning and memory and the levels of amyloidβ-protein(Aβ)and helper T cell 2(Th2)in the model rats with Alzheimer's disease(AD),and to clarify the effect of IL-33 in the scavenging of Aβin brain tissue of the model rats with AD and its mechanism.Methods:A total of 70 SD male rats were randomly divided into normal control group(intragastrical administration of double steaming water and subcutaneous injection of D-galactose),model group,sham operation group and extremely low dose,low dose,middle dose,high dose(0.01,0.10,1.00,and10.00 mg·L~(-1))of IL-33 groups(intragastrical administration of AlCl3 and subcutaneous injection of D-galactose);10 rats in each group.The agents were administered once daily for 60 d.After the last administration,step down test and Morris water maze experiment were used to detect the latency,the mistake times,the escape latencies,the resident time in target quadrant,and the swimming distance.After the behavioral testing,IL-33 was injected intracerebroventricularly for each dose of IL-33 group,and saline was injected intracerebroventricularly in the rats in sham operation group.ELISA method was used to detect the levels of Aβand Th2 in brain tissue of the rats.Results:The results of step down test showed that the latency of the rats in model group was obviously shortened(t=8.154,P<0.01)and the mistake times were significantly increased compared with normal control group(t=4.579,P<0.01).The results of Morris water maze test showed that the escape latency was obviously prolonged(t=27.810,P<0.01),the resident time in target quadrant and the distance of swimming of the rats in model group were significantly reduced compared with normal control group(t=3.767,P<0.01;t=1.973,P<0.05).The ELISA results showed that the level of Aβin brain tissue of the rats in model group was significantly increased(t=3.222,P<0.05)compared with normal control group,and the levels of Aβin the brain tissue of the rats in low,middle and high doses of IL-33 groups were significantly reduced compared with model group(P<0.05).The level of Th2 in brain tissue of the rats in model group was significantly decreased compared with normal control group(t=4.646,P<0.01),and the levels of Th2 in brain tissue of the rats in low,middle and high doses of IL-33 groups were significantly increased compared with model group(P<0.05).Conclusion:IL-33 has a scavenging effect on Aβin brain tissue of the AD model rats,and its mechanism may be related to the increase of Th2 level in brain tissue of the rats.
Objective:To explore the influence of interleukin-33(IL-33)on the abilities of spatial learning and memory and the levels of amyloidβ-protein(Aβ)and helper T cell 2(Th2)in the model rats with Alzheimer's disease(AD),and to clarify the effect of IL-33 in the scavenging of Aβin brain tissue of the model rats with AD and its mechanism.Methods:A total of 70 SD male rats were randomly divided into normal control group(intragastrical administration of double steaming water and subcutaneous injection of D-galactose),model group,sham operation group and extremely low dose,low dose,middle dose,high dose(0.01,0.10,1.00,and10.00 mg·L~(-1))of IL-33 groups(intragastrical administration of AlCl3 and subcutaneous injection of D-galactose);10 rats in each group.The agents were administered once daily for 60 d.After the last administration,step down test and Morris water maze experiment were used to detect the latency,the mistake times,the escape latencies,the resident time in target quadrant,and the swimming distance.After the behavioral testing,IL-33 was injected intracerebroventricularly for each dose of IL-33 group,and saline was injected intracerebroventricularly in the rats in sham operation group.ELISA method was used to detect the levels of Aβand Th2 in brain tissue of the rats.Results:The results of step down test showed that the latency of the rats in model group was obviously shortened(t=8.154,P<0.01)and the mistake times were significantly increased compared with normal control group(t=4.579,P<0.01).The results of Morris water maze test showed that the escape latency was obviously prolonged(t=27.810,P<0.01),the resident time in target quadrant and the distance of swimming of the rats in model group were significantly reduced compared with normal control group(t=3.767,P<0.01;t=1.973,P<0.05).The ELISA results showed that the level of Aβin brain tissue of the rats in model group was significantly increased(t=3.222,P<0.05)compared with normal control group,and the levels of Aβin the brain tissue of the rats in low,middle and high doses of IL-33 groups were significantly reduced compared with model group(P<0.05).The level of Th2 in brain tissue of the rats in model group was significantly decreased compared with normal control group(t=4.646,P<0.01),and the levels of Th2 in brain tissue of the rats in low,middle and high doses of IL-33 groups were significantly increased compared with model group(P<0.05).Conclusion:IL-33 has a scavenging effect on Aβin brain tissue of the AD model rats,and its mechanism may be related to the increase of Th2 level in brain tissue of the rats.
引文
[1]Campos-Pena V,Toral-Rios D,Becerril-Perez F,et al.Metabolic syndrome as a risk factor for Alzheimer’s disease:Is Aβa crucial factor in both pathologies?[J].Antioxid Redox Signal,2017,26(10):542-560.
[2]李倩,徐抒音,蔡艳,等.阿尔茨海默病老年斑相关研究进展[J].解剖学杂志,2016,39(3):365-368.
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[5]Chapuis J,Hot D,Hansamannel F,et al.Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer’s disease[J].Mol Psychiatry,2009,14(11):1004-1016.
[6]Deng W,Zheng MQ,Zhang J,et al.Effects of TFE from two species of Epimedium in Guizhou on the learning and memory abilities in dementia model rats[J].Chin Pharmacol Bull,2011,27(6):868-871.
[7]Li G,Yu J,Zhang L,et al.Onjisaponin B prevents cognitive impairment in a rat model of D-galactose-induced aging[J].Biomed Pharmacother,2018,9(99):113-120.
[8]Abdel-Aal RA,Assi AA,Kostandy BB.Rivastigmine reverses aluminum-induced behavioral changes in rats[J].Eur J Pharmacol,2011,659(2/3):169-176.
[9]钱绘,李根亮,李韬.市售含铝油条对大鼠行为及AD相关蛋白表达的影响[J].职业与健康,2018,34(5):604-607.
[10]杨吉平,赖红,赵海花,等.D-半乳糖联合染铝大鼠海马结构Aβ及相关蛋白的表达[J].神经解剖学杂志,2011,27(6):633-636.
[11]Gandhi S,Refolo LM,Sambamurti K.Amyloid precursor protein compartmentalization restricts beta-amyloid production:therapeutic targets based on BACE compartmentalization[J].J Mol Neurosci,2004,24(1):137-143.
[12]高雪明,李明才,王亚清,等.IL-33及其在中枢神经系统疾病中的作用[J].中国病理生理杂志,2012,28(10):1901-1905.
[13]刘善辉,张世超,尚吉戎.IL-33活性调节及在疾病中的调控作用[J].生物学杂志,2017,34(3):78-81.
[14]Fu AK,Hung KW,Yuen MY,et al.IL-33ameliorates Alzheimer’s disease-like pathology and cognitive decline[J].Proc Natl Acad Sci U S A,2016,113(19):E2705-E2713.
[15]Daria A,Colombo A,Llovera G,et al.Young microglia restore amyloid plaque clearance of aged microglia[J].EMBO J,2017,36(5):583-603.
[16]Song Y,Kim HD,Lee MK,et al.Maysin and its flavonoid derivative from Centipedegrass attenuates amyloid plaques by inducting humoral immune response with Th2Skewed cytokine response in the Tg(APPswe,PS1dE9)Alzheimer’s mouse model[J].PLoS One,2017,12(1):e0169509.
[17]Chackerian AA,Oldham ER,Murphy EE,et al.IL-1receptor accessory protein and ST2comprise the IL-33receptor complex[J].J Immunol,2007,179(4):2551-2555.
[18]Schmitz J,Owyang A,Oldham E,et al.IL-33,an interleukin-1-like cytokine that signals via the IL-1receptorrelated protein ST2and induces T helper type 2-associated cytokines[J].Immunity,2005,23(5):479-490.
[2]李倩,徐抒音,蔡艳,等.阿尔茨海默病老年斑相关研究进展[J].解剖学杂志,2016,39(3):365-368.
[3]向阳.阿尔茨海默病脑内Aβ的外周途径清除研究[D].重庆:第三军医大学,2016.
[4]Cayrol C,Girard JP.Interleukin-33(IL-33):A nuclear cytokine from the IL-1family[J].Immunol Rev,2018,281(1):154-168.
[5]Chapuis J,Hot D,Hansamannel F,et al.Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer’s disease[J].Mol Psychiatry,2009,14(11):1004-1016.
[6]Deng W,Zheng MQ,Zhang J,et al.Effects of TFE from two species of Epimedium in Guizhou on the learning and memory abilities in dementia model rats[J].Chin Pharmacol Bull,2011,27(6):868-871.
[7]Li G,Yu J,Zhang L,et al.Onjisaponin B prevents cognitive impairment in a rat model of D-galactose-induced aging[J].Biomed Pharmacother,2018,9(99):113-120.
[8]Abdel-Aal RA,Assi AA,Kostandy BB.Rivastigmine reverses aluminum-induced behavioral changes in rats[J].Eur J Pharmacol,2011,659(2/3):169-176.
[9]钱绘,李根亮,李韬.市售含铝油条对大鼠行为及AD相关蛋白表达的影响[J].职业与健康,2018,34(5):604-607.
[10]杨吉平,赖红,赵海花,等.D-半乳糖联合染铝大鼠海马结构Aβ及相关蛋白的表达[J].神经解剖学杂志,2011,27(6):633-636.
[11]Gandhi S,Refolo LM,Sambamurti K.Amyloid precursor protein compartmentalization restricts beta-amyloid production:therapeutic targets based on BACE compartmentalization[J].J Mol Neurosci,2004,24(1):137-143.
[12]高雪明,李明才,王亚清,等.IL-33及其在中枢神经系统疾病中的作用[J].中国病理生理杂志,2012,28(10):1901-1905.
[13]刘善辉,张世超,尚吉戎.IL-33活性调节及在疾病中的调控作用[J].生物学杂志,2017,34(3):78-81.
[14]Fu AK,Hung KW,Yuen MY,et al.IL-33ameliorates Alzheimer’s disease-like pathology and cognitive decline[J].Proc Natl Acad Sci U S A,2016,113(19):E2705-E2713.
[15]Daria A,Colombo A,Llovera G,et al.Young microglia restore amyloid plaque clearance of aged microglia[J].EMBO J,2017,36(5):583-603.
[16]Song Y,Kim HD,Lee MK,et al.Maysin and its flavonoid derivative from Centipedegrass attenuates amyloid plaques by inducting humoral immune response with Th2Skewed cytokine response in the Tg(APPswe,PS1dE9)Alzheimer’s mouse model[J].PLoS One,2017,12(1):e0169509.
[17]Chackerian AA,Oldham ER,Murphy EE,et al.IL-1receptor accessory protein and ST2comprise the IL-33receptor complex[J].J Immunol,2007,179(4):2551-2555.
[18]Schmitz J,Owyang A,Oldham E,et al.IL-33,an interleukin-1-like cytokine that signals via the IL-1receptorrelated protein ST2and induces T helper type 2-associated cytokines[J].Immunity,2005,23(5):479-490.