基于淀粉样蛋白代谢调控研究淫羊藿次苷Ⅱ抗阿尔茨海默病作用及机制

Ideal therapeutic drugs for Alzheimer’s disease (AD) are currently unavailable. The cause of the present drug with limited efficacy is probably due to aiming to single target, which is paradoxical to the complexity of AD pathogenesis. Hence, it is important to develop multi-target drugs targeting β-amyloid (Aβ) metabolism and its regulation based on the key role of Aβ in the pathogenesis of AD. Our previous study has demonstrated that icariin may be as a multi-target anti-AD agent, but its content in the brain is very little. It is speculated that the effect of icariin is probably duo to its active metabolite named icarisideⅡ(IRSⅡ). Therefore, this project is designed to firstly observe the effect of IRSⅡon AD in APP/PS1 mice, which express chimeric mouse/human Swedish mutant amyloid precursor protein (Mo/Hu APP695swe) and mutant human presenilin 1 protein (PS1-dE9). Then the effect of IRSⅡon formation of senile plaque and Aβ level is investigated in APP/PS1 mice. Base on the exact decrease of Aβ level by IRSⅡ, the effect of IRSⅡ on Aβ-originated pathway, including the expression of amyloid precursor protein (APP), APP-cleaved enzymes and the regulation of signal transduction pathway, is analyzed. At last, the effect of IRSⅡon Aβ-cleared pathway, especially for enzyme-degraded pathways and cell autophagy pathway, is investigated, and the effect of IRSⅡon the underlying signal pathways regulating autophagy is also analyzed. The project is aimed to quest for a multi-target anti-AD agent targeting Aβ metabolism and its regulation, and provide pharmacological basis for application of IRSⅡ into the treatment of AD.

目前尚无理想的阿尔茨海默病（AD）治疗药物。现有药物疗效有限的原因可能在于其作用靶点单一，与AD复杂的病理机制相悖。因此，基于淀粉样蛋白（Aβ）在AD发病中的关键作用，研究针对Aβ代谢调控的多靶点药物具有重要价值。前期研究发现，淫羊藿苷具有多靶点抗AD作用，但其在脑中的含量很少，推断其可能通过活性代谢产物淫羊藿次苷Ⅱ（IRSⅡ）发挥作用。所以，本项目首先通过APP/PS1转基因AD模式小鼠观察IRSⅡ的抗AD作用；然后考察IRSⅡ对AD模式小鼠老年斑形成及Aβ含量的影响；在明确IRSⅡ降低Aβ含量基础上，再观察IRSⅡ对Aβ产生途经包括APP及其裂解酶表达以及其调控信号通路影响；最后观察IRSⅡ对Aβ清除途经特别是酶降解途经及细胞自噬途经的影响，并分析IRSⅡ调控自噬可能的信号通路。该研究旨在针对Aβ代谢及其调控机制探索多靶点的AD治疗药物，为IRSⅡ用于AD的治疗提供基础药理学依据。

目前尚无理想的阿尔茨海默病（AD）治疗药物。现有药物疗效有限的原因可能在于其作用靶点单一，与AD复杂的病理机制相悖。因此，基于淀粉样蛋白（Aβ）在AD发病中的关键作用，研究针对Aβ代谢调控的多靶点药物具有重要价值。前期研究发现，淫羊藿苷具有多靶点抗AD作用，但其在脑中的含量很少，推断其可能通过活性代谢产物淫羊藿次苷Ⅱ（ICSⅡ）发挥作用。本研究发现：（1）ICS II可明显减轻APP/PS1转基因AD模式小鼠的学习记忆减退、海马神经元缺失及老年斑形成，其作用机制至少与抑制Aβ产生及降低PDE 5含量有关。（2）ICSⅡ可明显减轻Aβ25-35 所致的大鼠学习记忆减退及凋亡，其机制可能与降低PDE 5的含量及上调BDNF/TrkB/CREB 信号通路有关。（3）ICS II明显减轻链脲佐菌素诱导的大鼠学习记忆减退及海马神经元的形态学损伤，其机制可能与下调APP、BACE1的蛋白表达和上调NEP的蛋白表达从而抑制Aβ产生和促进Aβ代谢，减少炎性因子的产生，抑制IκB-α的降解和NF-κB p65的磷酸化有关。（4）ICS II能够明显改善Aβ25-35诱导的神经细胞损伤，其作用机制与调控BDNF/TrkB/CREB信号通路有关。（5）ICS Ⅱ 通过调节IKK/IκB/NF-κB/BACE1信号通路减轻脂多糖诱导的星形胶质细胞炎症。该研究针对Aβ代谢及其调控机制探索多靶点的AD治疗药物，为ICSⅡ用于AD的治疗提供了基础药理学依据。