在老龄化日趋显著的背景下，阿尔茨海默病（AD）已成为严重的社会公共卫生问题，目前尚缺少有效的治疗药物。淀粉样β蛋白（Aβ）异常聚集为其特征性病理改变之一，是一系列神经毒性的始发因素。以往研究证实淫羊藿苷（ICA）对AD有一定的防治作用，但因生物利用度差等因素，直接开发为药物的潜在性不高。淫羊藿素（ICT）作为ICA的体内主要代谢产物之一，分子结构较小，已有体外研究报道其有神经细胞保护作用。我们前期研究发现，ICT具有改善Aβ25-35所致AD模型大鼠记忆、降低海马内Aβ水平的作用，提示ICT作用于Aβ通路的潜在性。本项目拟通过APP/PS1转基因AD模型小鼠在体实验和离体细胞实验，观察ICT的药效及检测ICT对APP-Aβ代谢通路中主要酶类及代谢产物的影响，尤其是对关键酶β位淀粉样前体蛋白裂解酶（BACE-1）的调控作用，以探讨ICT抗AD的作用机制，对寻找临床防治AD的药物具有重要意义。

Alzheimer's disease (AD) becomes an more severe clinical and public problem in the modern society with increasingly aged population. A wealth of evidence suggests that Aβ plays a central role in the pathogenesis of AD and triggers down-stream neurotoxic processes. BACE-1 is the rate-limiting enzyme which cleaves APP at the β-site to produce the Aβ peptides. Our previous studies have shown that Icarrin has protective effects on AD. However, it is difficult to further develop Icarrin into an anti-AD drug due to its low bioavalability, low solubility, and low chemical stability. As a primary metabolite from Icarrin, Icartin (ICT) is much smaller in size and displays similarly protective effects on AD as Icarrin. However, the mechanism of how ICT functions against AD remains unclear. Our prelimilary data suggests that treatments of ICT reduce hippocampal Aβ levels and rescue Aβ-induced cognitive defects in AD rat models. In this proposal, we will further explore the roles of ICT in regulating Aβ generated pathways, especially in BACE-1 regulation. This study will bring novel insights into the mechanisms of the neuroprotective roles of ICT in preclinical AD animal models, facilitating the development of clinical preventions and treatments for AD.

阿尔茨海默病（AD）是一种常见于老年前期和老年期的渐进性大脑退行性疾病，目前尚缺乏AD治疗的特效药物。我们的研究发现，从本地区常用中药淫羊藿中提取的有效成分淫羊藿苷具有防治AD的作用，其体内主要代谢产物淫羊藿素(Icartin，ICT)分子结构更小，亦可显著改善AD模型鼠的学习记忆功能，并降低海马Aβ的水平。然而，目前尚未见ICT是如何降低Aβ水平而产生抗AD作用的研究报道。本项目拟通过APP/PS1转基因人胚肾细胞（APP-PS1-HEK293）以及BACE1质粒转染的APP-PS1-HEK293细胞模型，考察ICT对相关因子的调控。为了使ICT的作用更直观和直接，课题也将采用细胞模型对APP、BACE1进行过表达后，研究ICT的作用及对关键因子的调控。研究发现，在BACE1质粒转染的APP-PS1-HEK293细胞中，ICT可以通过升高α-secretase酶活性，降低BACE1和PS1酶活性；升高α-secretase蛋白水平，降低BACE1和PS1蛋白水平；以及抑制Aβ生成相关基因的转录，同时升高Aβ清除相关基因的转录，从而使Aβ生成降低。