更年春方防治阿尔茨海默病的分子机制

More and more postmenopausal women attacked by Alzheimer's disease, however there isn't any drug that has certainly effectivity on AD. Chinese herb and estrogen therapy has taken more and more attention. The previous studies suggested that Gengnianchu recipe was effective to treat the perimenopausal syndrom and ameliorate the memory ability. It increased the score of ovariectomized Sprague-Dawley (SD) rats taking Morris water maze test and protected the PC12 cells insulted from Amyloid beta. For the further research of GNC's effectivity on AD and its mechanisms, we take the Alzheimer's disease modle in vivo(APP/PS1 double-transgenic mice) and in vitro(hipocampal cells insulted from Aβ). Morris water maze test, cell morphology, cell apoptosis, ER subtype and the key moleculars of signal transduction pathway, related moleculars of Treg cells will be detected. The expression of ER subtypes and its signal transduction pathway will be analyzed by observing the GNC's effect on AD in animal level, cell level and molecular level. Also the effect of Treg cells on AD and the effect of GNC on Treg cells will be studied which may show us the mechanism of GNC's effect on AD and its regulation on neuro-endocrine-immunity system. Meanwhile, the chemical ingredients of the whole recipe will be studied systemically to detect its effective ingredients on AD and to provid scientific basis for making a guidline on how to use GNC recipe clinically and its quality control.

绝经后妇女阿尔茨海默病（AD）发病率明显增加，治疗AD尚处对症阶段，中医药和雌激素防治AD正引起重视。我们前期发现对围绝经期综合征有疗效且可增强记忆力的补肾为主中药更年春(GNC)方可提高卵巢切除大鼠Morris水迷宫成绩，对β淀粉样蛋白（Aβ）致具有神经细胞特性的PC12细胞损伤有保护作用。为进一步研究GNC对AD的疗效及机理,我们拟以APP/ PS1 双转基因AD 小鼠作为AD在体模型, 以Aβ作用胎鼠海马神经元构建AD体外模型,通过Morris水迷宫、海马形态学及凋亡观察、ER亚型、信号转导途径关键信号分子、Treg细胞功能相关分子的检测，观察GNC对AD的影响,分析GNC作用下优势表达的ER亚型及作用的信号转导途径，探讨Treg对AD的影响及GNC对Treg的作用，解析GNC对神经内分泌免疫的调节,同时对GNC整方化学成分进行系统研究，阐明其作用的有效成分，为质量控制提供科学依据。

绝经后妇女阿尔茨海默病（AD）发病率明显增加，治疗AD尚处对症阶段，中医药防治AD正引起重视。我们前期发现对围绝经期综合征有疗效且可增强记忆力的补肾为主中药更年春(GNC)方可提高卵巢切除大鼠Morris水迷宫成绩，对β淀粉样蛋白（Aβ）致具有神经细胞特性的PC12细胞损伤有保护作用。为进一步研究GNC对AD的疗效及机理,我们以APP/PS1双转基因模型小鼠为研究对象, 在体研究更年春方对神经的保护作用、对AD的防治及其作用机理，结果表明GNC能够改善APP/PS1双转基因小鼠的学习记忆能力，并显著抑制APP/PS1双转基因小鼠脑内的神经元凋亡，上调Bcl-2蛋白和降低Bax蛋白表达，可能是通过降低JNK/SAPK的磷酸化水平实现的。GNC可以降低炎性因子水平，可能是通过降低NF-κB p65的磷酸化水平，从而达到改善神经炎性反应的作用。体外实验发现，Aβ1-42可激活BV-2细胞，显著提高炎性因子的表达，GNC含药血清可抑制Aβ1-42对BV-2细胞的激活作用，可能是通过够降低JNK/SAPK和NF-κB p65的磷酸化水平来抑制小胶质细胞的激活，改善AD的神经炎性反应，从而起到保护神经元的作用。同时，我们以线虫为研究对象，探讨了传统中药更年春方抗衰老、抗氧化应激以及抗Aβ毒性等方面的作用。通过野生型线虫的寿命实验，发现更年春方延长线虫寿命。利用重金属Cr氧化应激模型， 显示更年春方通过调节DAF16/FOXO提高线虫抗氧化应激能力。利用AD转基因线虫CL4176,显示更年春方提高抗氧化应激能力，减少β样淀粉蛋白表达，我们推测这也是更年春方防治AD可能的保护机制。