多奈哌齐未能改善APP/PS1-AD转基因小鼠学习记忆功能的机制研究

APP/PS1-AD transgenic mice can not used to evaluate the therapeutic effect of donepezil

目的探索多奈哌齐未能改善APP/PS1-AD转基因小鼠学习记忆功能的机制。方法选用9月龄野生型及APP/PS1-AD转基因小鼠分成野生型小鼠对照组、转基因小鼠对照组、转基因小鼠多奈哌齐1mg/kg组、转基因小鼠多奈哌齐3mg/kg组和转基因小鼠多奈哌齐6mg/kg组,每组20只,连续给药12周后实验动物心脏取血和分离其大脑皮层及海马组织,检测脑组织乙酰胆碱酯酶活性及β-淀粉样蛋白(Aβ)42含量,测定小鼠脑组织金属离子含量,采用免疫荧光法检测脑内Aβ42淀粉样斑块沉积现象。结果多奈哌齐可显著降低APP/PS1-AD转基因小鼠大脑皮层组织的乙酰胆碱酯酶活性(P<0.01),且各剂量组作用强度相似,但对小鼠海马组织中乙酰胆碱酯酶活性没有显著影响;Aβ42检测结果显示,多奈哌齐对各剂量组转基因小鼠的皮层和海马组织中Aβ42含量无明显影响;免疫荧光法检测结果显示,多奈哌齐长期给药未能显著减少Aβ42淀粉样斑块沉积;原子吸收光谱法测定结果显示,多奈哌齐对转基因小鼠大脑皮层组织镁离子、铜离子和钙离子浓度无明显影响。结论APP/PS1-AD转基因模型小鼠不能用于评价多奈哌齐类药物的药效。

Objective To evaluate the mechanism of donepezil failing to improve the learning and memory ability in APP/PS1-AD transgenic mice.Methods One hundred mice with 9 months of age were randomly divided into 5 groups with 20 in each group:wide type control group(WT control),transgenic control(Tg control),and 3 treatment groups of APP/PS1-AD transgenic mice(treated with donepezil 1mg/kg,3mg/kg and 6mg/kg for 12 weeks).The activity of acetylcholinesterase and the quantity of amyloidβprotein(Aβ)42 in the brain tissue were detected.The quantity of metal ions in the whole blood and brain tissue were measured,and the deposition of Aβ42 protein plapues in the brain was evaluated by immunofluorescence.Results Donepezil significantly reduced the activity of acetylcholinesterase in the cerebral cortex of APP/PS1-AD transgenic mice(P<0.01),and the action intensity of each dose group was similar,but there was no significant effect on the activity of acetylcholinesterase in the hippocampus of mice.The test results showed that donepezil had no significant effect on the content of Aβ42 in the cortex and hippocampus of the mice,and the immunofluorescence test showed that the long-term administration of donepezil did not significantly reduce the deposition of Aβ42 protein plaques;the results of atomic absorption spectrometry showed that donepezil had no effect on the concentration of Mg,Cu and Ca in cerebral cortex of the transgenic mice.Conclusion The Alzheimer's disease model APP/PS1-AD transgenic mice can not be used to evaluate the efficacy of donepezil as a therapeutic agent.