基于“肾-髓-脑”相关理论探讨益肾化浊法通过调控Aβ“产生与清除平衡”抑制脑内Aβ过度沉积治疗AD的作用机制研究

β-amyloid protein (Aβ) overdeposition in the brain is the primary and central factor in the development of Alzheimer’s disease (AD), which is mainly caused by the imbalance of Aβ production and clearance. This study aim to do further research on inhibiting Aβ over-deposition in brain from regulating the balance of Aβ production and clearanceto based on Yishen Huazhuo method (YSHZ) improving cognitive function of AD patients, inhibition of neuronal apoptosis and against Aβ toxic injury. AD model rats were used as a research object, and YSHZ method was used as an intervention method. Animal behavior, morphology, immunohistochemistry, ELISA, Western blot and RT-PCR were used to detect the effects on cognitive function of AD rats, neuron and synaptic structure, Aβ content in brain, peripheral blood and urine, and influence on key targets in the process of Aβ production, central clearance, the blood-brain barrier (BBB) transport, and peripheral clearance, in order to investigate the mechanism of YSHZ’s treatment of AD through regulating the balance of Aβ “generation and clearance” to inhibit Aβ overdeposition in brain from the levels of animals, tissues, cells and molecular biology, which provides experimental basis for its clinical application, and provides support for some explanations of the related theory of “kidney-marrow-brain”.

脑内β淀粉样蛋白（Aβ）过度沉积是阿尔兹海默病（AD）发生发展的始动因素和核心环节，其主要原因为Aβ的“产生与清除失衡”。本课题在前期益肾化浊法（YSHZ）改善AD患者认知功能、抑制神经元凋亡、抗Aβ毒性损伤的基础上，拟从调控Aβ“产生与清除平衡”，抑制脑内Aβ过度沉积方面做进一步深入研究。拟采用AD模型大鼠为研究对象，以YSHZ为干预手段，通过动物行为学、形态学、免疫组化、ELISA、Western blot及RT-PCR等实验方法，考察YSHZ对AD大鼠认知功能、神经元及突触结构、脑内、外周血和尿液中的Aβ含量、以及Aβ生成、中枢清除、血脑屏障转运、外周清除等过程中关键靶点的影响，从整体动物、组织、细胞、分子生物等不同水平探讨YSHZ通过调控Aβ“产生与清除平衡”，抑制脑内Aβ过度沉积治疗AD的作用机制，为其临床应用提供实验依据，并为部分阐释中医“肾-髓-脑”相关理论提供支撑。

阿尔兹海默病（AD）属于祖国医学“呆症”、“不慧”、“善忘”等病证范畴。“肾虚精亏、髓海空虚”是AD 形成的基本病机。本课题组紧紧抓住“肾虚”为本、“痰瘀”、“浊毒”为标的病机，方从法出，法由证立，选用益肾化浊法治疗，“益肾”以治本，“化浊”以治标，扶正祛邪兼顾，取得了显著疗效。脑内β淀粉样蛋白（Aβ）过度沉积AD发生发展的始动因素和核心环节，其主要原因为Aβ的“产生与清除失衡”。本项目在前期益肾化浊法（YSHZ）改善AD患者认知功能、抑制神经元凋亡、抗Aβ毒性损伤的基础上，从调控Aβ“产生与清除平衡”，抑制脑内Aβ过度沉积方面做进一步深入研究。通过侧脑室注射Aβ建立大鼠AD模型，以YSHZ为干预手段，通过动物行为学、形态学、免疫组化、ELISA、Western blot及RT-PCR等实验方法，考察YSHZ对AD大鼠认知功能、神经元及突触结构、脑内、外周血和尿液中的Aβ含量、以及Aβ生成、中枢清除、血脑屏障（BBB）转运、外周清除等过程中关键靶点的影响。结果表明，益肾化浊法可有效改善AD大鼠的认知功能，并降低脑内Aβ含量。其作用机制包括促进Aβ非淀粉样水解途径，促进脑内Aβ通过BBB转运至外周血，并通过改善肾功能而促进肾脏清除外周Aβ。从整体动物、组织、细胞、分子生物等不同水平探讨YSHZ通过调控Aβ“产生与清除平衡”，抑制脑内Aβ过度沉积治疗AD的作用机制，为其临床应用提供实验依据，并为部分阐释中医“肾-髓-脑”相关理论提供支撑。发表SCI期刊论文1篇，国内核心期刊论文1篇；培养博士研究生1名。