Abstract: Objective To investigate the effects of early intervention with different doses of hesperetin on learning and memory ability, amyloid beta protein 1-42(Aβ42) and neprilysin (NEP) activity in APPswe/PS1dE9 double transgenic mice. Methods Three month old C57BL/6J wild-type mice were used as control group(0.5% CMC-Na), and three month old APPswe/PS1dE9 double transgenic mice were used as model group, hesperetin low, medium and high dose groups (0, 20, 40 and 80 mg/kg/d), respectively. They were gavaged once a day for 6 months. Morris water maze behavior test was used to observe the learning and memory ability of mice; HE staining was used to observe the morphology of hippocampal neurons; ELISA was used to detect the content of Aβ 42 in serum; Western blot was used to detect the expression of Aβ 42 and neprilysin (NEP) in brain tissue. Results Compared with the control group, the incubation period of mice in the model group was significantly prolonged(P<0.05), the number of crossing platforms was reduced(P<0.05), the neurons in the hippocampal CA1 area were significantly damaged, the serum Aβ42 content was significantly increased(P<0.05), the content of Aβ42 in the brain tissue was significantly increased(P<0.01), and there was no significant difference in the content of NEP. Compared with the model group, the incubation period of mice in the low, medium and high dose groups of hesperetin was significantly shortened(P<0.01). The number of times increased(P<0.01), the morphological structure of hippocampal CA1 neurons was significantly improved, the content of Aβ42 in serum was significantly reduced(P<0.01), the content of Aβ42 in brain tissue was significantly reduced(P<0.01). The NEP content in the medium and high dose group were significantly increased(P<0.01). Conclusion Early intervention of hesperetin could significantly improve the learning and memory ability of APPswe/PS1dE9 double transgenic mice and neuronal damage in hippocampus CA1 area. The mechanism might be related to the increase of NEP activity and the enhancement of Aβ42 metabolism.

Key words: Alzheimer's disease, hesperetin, amyloid β-protein;, neprilysin

摘要： 目的 探究不同剂量橙皮素(hesperetin)早期干预对APPswe/PS1dE9双转基因小鼠学习记忆能力、β-淀粉样蛋白(1-42)(amyloid β-protein1-42,Aβ42)及Aβ降解酶脑啡肽酶(neprilysin,NEP) 活性的影响。方法 设立三月龄C57BL/6J野生型小鼠为对照组(0.5%CMC-Na),三月龄APPswe/PS1dE9双转基因小鼠分别为模型组、橙皮素低、中、高剂量组(0、20、40、80mg/kg/d),灌胃1次/d,连续6个月。采用Morris水迷宫行为学实验观察小鼠的学习记忆能力;HE染色观察小鼠海马神经元形态;ELISA法检测小鼠血清中Aβ42含量;蛋白印迹法(Western Blot)检测小鼠脑组织Aβ42、脑啡肽酶(NEP)的表达。结果 与对照组相比,模型组小鼠寻找平台潜伏期明显延长(P<0.05),穿越平台次数减少(P<0.05),海马CA1区神经元有明显损伤,血清中Aβ42含量明显增加(P<0.05),脑组织中Aβ42含量明显增加(P<0.01)、NEP含量无明显差异;与模型组相比,橙皮素低、中、高剂量组小鼠潜伏期明显缩短(P<0.01),穿越平台次数增加(P<0.01),海马CA1区神经元形态结构有明显改善,血清中Aβ42含量明显降低(P<0.01),脑组织中Aβ42含量明显降低(P<0.01)、橙皮素中、高剂量组NEP含量明显升高(P<0.01)。结论 橙皮素早期干预能明显改善APPswe/PS1dE9双转基因小鼠学习记忆能力和海马CA1区神经元损伤,其机制可能与提高NEP活性,增强Aβ42代谢有关。

关键词: 阿尔茨海默病, 橙皮素, β-淀粉样蛋白;, 脑啡肽酶