| 严 琪,杜 婴,赵 超,张 卓,杨艾利,苗建亭,李柱一.SB239063对APPswe/PS1dE9小鼠Aβ生成的调控作用及机制研究[J].,2017,17(10):1827-1833 |
| SB239063对APPswe/PS1dE9小鼠Aβ生成的调控作用及机制研究 |
| The Effect and Molecular Mechanisms of SB239063 on Regulating Aβ Generation in APPswe/PS1dE9 Mice |
| 投稿时间：2016-10-25 修订日期：2016-11-20 |
| DOI：10.13241/j.cnki.pmb.2017.10.007 |
| 中文关键词: 阿尔茨海默病 p38丝裂原活化蛋白激酶 β淀粉样蛋白 β位点APP裂解酶1 早老素1 |
| 英文关键词: Alzheimer's disease P38MAPK β-amyloid BACE1 PS1 |
| 基金项目:国家自然科学基金项目（面上项目）（81471111） |
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| 中文摘要: |
| 摘要 目的：探讨p38MAPK抑制剂SB239063对AD模型小鼠认知功能障碍及其脑内β-淀粉样蛋白（beta-amyloid protein, Aβ）表达情况的影响。方法：采用6月龄APPswe/PS1dE9（APP/PS1）双转基因雄性AD模型小鼠及同龄野生型（WT）C57BL/6J小鼠为研究对象，将小鼠随机分为SB239063-WT治疗组、WT对照组、SB239063-APP/PS1治疗组和APP/PS1对照组，治疗组小鼠接受腹腔注射SB239063药物溶液（用3%DMSO生理盐水溶液溶解，给药剂量为15 mg/kg），对照组小鼠接受腹腔注射相应体积的3%DMSO生理盐水溶液，1次/日连续给药6周。采用Morris水迷宫、蛋白质印迹法（Western Blot）和酶联免疫吸附法（ELISA）分别评估各组小鼠学习记忆功能、Aβ含量及其相关酶β-位点APP裂解酶1（BACE1）、早老素1（PS1）的表达水平。结果：水迷宫结果显示，与APP/PS1对照组相比，SB239063慢性治疗可以明显缩短APP/PS1小鼠找到隐藏平台所需的潜伏期（P＜0.01），增加APP/PS1小鼠在目标象限停留时间百分比（P＜0.01）和穿越原平台区域的次数（P＜0.01）；ELISA结果显示，给予SB239063治疗能够显著减少AD小鼠脑内可溶性Aβ1-42（P＜0.05）、Aβ1-40（P＜0.05）和Aβ寡聚体（P＜0.01）的含量；Western blot 结果显示，给予SB239063治疗后APP/PS1小鼠脑内皮层和海马组织中的p-p38MAPK（P＜0.01）、BACE1（P＜0.01）、PS1（P＜0.01）的表达水平明显下降。结论：SB239063可能通过下调p38MAPK的磷酸化水平抑制BACE1和PS1的表达，从而减少Aβ的生成并且改善AD小鼠的学习记忆功能损害，提示SB239063对A?茁所造成的病理损害具有潜在的治疗作用。 |
| 英文摘要: |
| ABSTRACT Objective: To investigate the efficacy and molecular mechanisms of SB239063 on cognitive deficits and Aβ generation in APPswe/PS1dE9 mice. Methods: Six-month-old male APPswe/PS1dE9 mice and their wild-type littermates were randomized into SB239063-treatedgroups and control groups respectively. The treated groups received SB239063(dissolved in 3% DMSO at a dose of 15mg/kg) once per day by intraperitoneal injection, whereas the control groups received an equal volume of 3% DMSO once per day by intraperitoneal injection. Six weeks after the treatments, the spatial learning and memory ability of all mice were evaluated by the Morris water maze test, the levels of soluble Aβ were detected with enzyme-linked immunosorbent assay (ELISA) kits, the expression of crucial enzymes in the production of Aβ were tested with western blot method. Results: Compared with the vehicle-treated APPswe/PS1dE9 mice, the escape latency in reaching the hidden-platform were significantly decreased (P<0.01), while the percentage of time spend in the target quadrant (P<0.01) and the frequency of crossing the platform (P<0.01) were potently increased in SB239063-treated APPswe/PS1dE9 mice(P<0.01). Meanwhile, the levels of soluble Aβ1-42(P<0.05), Aβ1-40(P<0.05) and Aβ oligomers(P<0.01) were dramatically decreased in SB239063-treated APPswe/PS1dE9 mice versus the control group. In addition, the expression of p-p38MAPK, BACE1 and PS1 in APPswe/PS1dE9 mice were markedly reduced by SB239063 treatment (P<0.01). Conclusion: SB239063 can reverse cognitive impairments and Aβ toxicity by decreasing the expression of BACE1 and PS1 which may result from inhibition of p-p38MAPK. Our findings provide that SB239063 may be a promising therapeutic strategy for the treatment of AD. |
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