姜黄素对APPswe/PS1dE9双转基因小鼠Aβ生成和降解的影响

目的观察姜黄素对APPswe/PS1dE9双转基因小鼠β淀粉样蛋白(βamyloid,Aβ)生成酶早老素2(presenilin2,PS2)和Aβ降解酶胰岛素降解酶(insulin degrading enzyme,IDE)表达的影响,探讨姜黄素在AD防治中的机制。方法将3月龄的APPswe/PS1dE9双转基因小鼠随机分为模型组、阳性对照组罗格列酮组,0.92mg/(kg·d)]、姜黄素大400mg/(kg·d)]、中200mg/(kg·d)]、小100mg/(kg·d)]剂量组,每组10只;并以同月龄遗传背景相同的C57BL/6J小鼠作为正常对照组10只。每天灌胃给药1次,模型组和正常对照组用等体积0.5%羧甲基纤维素(carboxymethyl cellulose,CMC)灌胃。灌胃3个月后,应用Morris水迷宫、免疫组织化学等方法,检测动物的学习记忆能力、海马Aβ生成酶PS2和降解酶IDE表达变化。结果行为学检测,模型组小鼠的游泳轨迹多为边缘型,而正常对照组、阳性对照组、姜黄素各组小鼠的游泳轨迹多为趋向型和直线型。Aβ生成酶PS2和降解酶IDE的免疫组织化学染色结果,模型组小鼠海马CA1区PS2阳性细胞较正常对照组明显增加(P0.01),与模型组相比,姜黄素各组小鼠海马CA1区PS2阳性细胞减少(P0.01)。模型组小鼠海马CA1区PS2阳性细胞平均灰度值较正常对照组降低(P0.05),姜黄素小剂量组阳性细胞平均灰度值同模型组相比明显增加(P0.01)。模型组小鼠海马CA1区IDE阳性细胞较正常对照组明显减少(P0.01),与模型组相比,姜黄素中剂量组小鼠海马CA1区IDE阳性细胞明显增加(P0.05)。模型组小鼠海马CA1区IDE阳性细胞平均灰度值较正常对照组明显增加(P0.01),姜黄素各组小鼠海马CA1区IDE阳性细胞平均灰度值同模型组相比均明显降低(P0.01)。结论姜黄素能通过减少Aβ生成酶和增加Aβ降解酶的表达,降低Aβ蛋白的表达进而改善APPswe/PS1dE9双转基因小鼠的学习记忆能力。

Effect of Curcumin on Production and Degradation of Aβ in APPswe/PS1 dE9 Double Transgenic Mice

Objective To observe the effect of curcumin on the expression of Aβ synthase and Aβ-degrading enzyme IDE in APPswe /PS1dE9 double transgenic mice and investigate the mechanisms of curcumin in prevention and treatment of Alzheimer＇s disease （AD）.Methods 3-month old APPswe /PS1dE9 dtg mice were randomly divided into model group,positive control group （Rosiglitazone group,0.92 mg /kg·d） and high dose curcumin （400 mg /kg·d）,moderate dose （200 mg /kg·d） and low dose （100 mg /kg·d） groups （n=10）,with C57BL /6J mice of the same age and genetic background as normal control group,n=10.Medication was given once a day by intragastric administration while the model group and normal control group received an equal volume of 0.5% carboxymethyl cellulose.After 3 months,Morris water maze was used to assess the learning and memory abilities of animals,and the changes of expression of hippocampal Aβ synthetase and PS2-degrading enzyme IDE were detected by immunohistochemistry.Results The behavior test revealed that most model mice showed peripheral type swimming,while the mice of normal control,positive control,high dose curcumin,moderate dose and low dose groups showed trend type and linear type swimming.The immunohistochemical staining of the expression of Aβ42 synthetase and PS2 degrading enzyme IDE showed that PS2positive cells in the hippocampal CA1 area were significantly increased in model mice compared with those in the normal control group （P0.01）.Compared with the model group,PS2-positive cells in hippocampal CA1 area of all curcumin groups were significantly decreased （P0.01）,that in model mice was increased in the normal control group （P0.05）,and the average gray value of positive cells in low dose curcumin group was significantly increased compared with that in the model group （P0.01）.IDE-positive cells in the hippocampal CA1 area were significantly decreased in the model mice than that in the normal control group （P0.01）.Compared with the model group,IDE-positive cells in the hippocampal CA1 area were significantly increased in the moderate dose curcumin group （P0.05）.The average gray value of IDE-positive cells in hippocampal CA1 area was significantly increased in the model mice compared with that of normal control group （P0.01）,and the average gray value of IDE-positive cells in hippocampal CA1 area was significantly lower in all curcumin groups compared with that in the model group （P0.01）.Conclusion Curcumin can improve the learning and memory abilities of APPswe /PS1dE9 doublet transgenic mice through decreasing the expression of Aβ synthetase and increasing the expression of Aβ-degrading enzyme,thus decreasing the expression of Aβ protein.