新型细辛醚衍生物促进线粒体自噬治疗阿尔茨海默病的作用和机制

There is no effective cure for Alzheimer’s disease (AD) which is a common neurodegenerative disorder. Reducing neuronal apoptosis and promoting neural stem cell (NSC) proliferation has been recognized as two important therapeutic avenues, which are regulated by mitophagy. We have previously shown that asarone, which is a major active constituent in Acorus tatarinowii, promotes NSC proliferation and ameliorates AD pathogenesis. Following these findings, we further developed a novel derivative of asarone, PYC-1, and found that amyloid-beta (Abeta)-induced impairment in mitophagy and NSC proliferation can be partially restored by PYC-1. We hypothesis that reducing neuronal apoptosis, as well as promoting NSC proliferation and neurogenesis by enhancing mitophagy, may be important pharmacological mechanisms to explain the anti-AD effect of PYC-1. In this study, we will use human iPSC-derived neuron, neural stem cells and AD organoids, as well as AD transgenic mice, to test whether and how mitophagy is regulated by PYC-1. Furthermore, we will study whether the effect of PYC-1 on mitophagy is mediated by AMPK/ULK1 signaling. Our study not only provides new evidences for deep insight into the effects of natural products and their derivatives on AD, but also offers new avenues for AD treatment.

临床上对神经退行性疾病-阿尔茨海默病（AD）尚缺乏有效的治疗手段。抑制神经元凋亡和促进神经干细胞（NSC）介导的神经发生是缓解AD的重要手段。这两个过程都受到线粒体自噬调控。前期发表工作发现芳香开窍中药石菖蒲的主要活性成分细辛醚促进NSC增殖并改善AD小鼠症状。进一步分子改造后获得的新型衍生物PYC-1，能逆转beta淀粉样蛋白导致的线粒体自噬和NSC增殖受损。因此我们推测：PYC-1能够通过促进线粒体自噬来抑制神经元凋亡和提高NSC增殖与神经发生，并发挥缓解AD发病的作用。本项目拟利用人iPSC诱导的神经元和NSC、类脑器官AD模型以及小鼠AD模型，从线粒体自噬作为多种AD致病因素的机制汇聚节点的角度，研究PYC-1改善AD的作用和机制，并进一步探讨PYC-1通过AMPK/ULK1信号通路调节线粒体自噬的可能性，为理解天然产物及衍生物的抗AD作用及发展疾病防治新方法提供思路。

临床上对神经退行性疾病-阿尔茨海默病（AD）尚缺乏有效的治疗手段。研究表明，阿尔茨海默病患者大脑中的线粒体功能受损，这可能导致神经元受损和死亡。而线粒体自噬是一种细胞的自清除机制，可以清除细胞中的损坏或不需要的线粒体，进而改善总体线粒体功能。临床上观察到AD发病过程中也伴随着线粒体自噬功能的显著下降，因此通过药物等手段改善线粒体自噬，可能是AD的重要治疗手段。本课题执行期间，为了在更接近真实人脑的实验体系中研究线粒体自噬过程，我们开发了多种新型人源类脑器官AD模型，成功模拟了AD病人大脑中线粒体自噬受损的临床病理现象。同时通过在上述体系中对AD相关线粒体自噬水平的检测，我们在天然产物及其衍生物中发现了高效的线粒体自噬促进剂及其作用分子机制，并验证了其对AD相关病理的改善效果，为AD提供了新的潜在治疗手段。