纤毛糖苷A通过激活线粒体自噬和抑制NLRP3炎性小体激活来减轻阿尔茨海默病中的神经炎症。

Ciliatoside A attenuates neuroinflammation in Alzheimer's disease by activating mitophagy and inhibiting NLRP3 inflammasome activation.

作者信息

Guo Minsong, Wang Zhengqin, Zhou Xiaogang, Yu Chonglin, Wu Jianming, Yu Lu, Mi Jianing, Ren Fang, Law Betty Yuen Kwan, Pan Hudan, Wong Vincent Kam Wai, Qin Dalian, Wu Anguo

机构信息

Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Department of Cardiology, the Affiliated Hospital of Southwest Medical University and Key Laboratory of Medical Electrophysiology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong, China.

出版信息

Phytomedicine. 2025 Jun 7;145:156928. doi: 10.1016/j.phymed.2025.156928.

DOI:10.1016/j.phymed.2025.156928

PMID:40541122

Abstract

BACKGROUND

Alzheimer's disease (AD) is a gradually worsening neurological condition that involves memory loss, brain inflammation, and impaired mitochondrial function. The NLRP3 inflammasome activation in microglia plays a pivotal role in promoting neuroinflammation and worsening disease progression. Mitochondrial dysfunction and impaired mitophagy further create a detrimental feedback loop of oxidative stress and inflammation. Despite extensive research, pharmacological agents capable of simultaneously targeting both NLRP3 inflammasome activation and impaired mitophagy remain scarce.

METHODS

We explored the therapeutic potential of Ciliatoside A (CA), a novel natural compound isolated from Peristrophe japonica, utilizing comprehensive cellular and animal models. In lipopolysaccharide/nigericin (LPS/Nig)-stimulated BV-2 microglial cells, the impact of CA on inflammasome activation, pyroptosis, mitochondrial health, and oxidative stress was assessed. Mechanistic evaluations were conducted using Western blotting, immunofluorescence, and advanced mitophagy assays. Furthermore, the efficacy of CA was validated in Caenorhabditis elegans (C. elegans) models expressing human amyloid-beta (Aβ) and the well-established 3xTg-AD mouse model.

RESULTS

Our results demonstrate CA effectively inhibits NLRP3 inflammasome activation, reduces microglial pyroptosis, and mitigates oxidative stress-induced mitochondrial impairment in BV-2 cells. Notably, we identified the AMPK/ULK1 and PINK1/Parkin pathways as novel targets through which CA robustly activates mitophagy. Consistent therapeutic effects were observed in vivo, with CA significantly reducing Aβ-induced paralysis, ROS generation, and enhancing autophagy in worms. In 3xTg-AD mice, CA markedly improved cognitive function, diminished Aβ plaque deposition, alleviated neuroinflammation, and preserved neuronal integrity.

CONCLUSION

For the first time, this study reveals that CA offers dual neuroprotective benefits by promoting mitophagy while inhibiting NLRP3 inflammasome-mediated neuroinflammation. These novel insights highlight the innovative therapeutic potential of CA, suggesting its promising application in slowing AD progression and mitigating its pathological features.

摘要

背景

阿尔茨海默病（AD）是一种逐渐恶化的神经疾病，涉及记忆丧失、脑部炎症和线粒体功能受损。小胶质细胞中的NLRP3炎性小体激活在促进神经炎症和恶化疾病进展中起关键作用。线粒体功能障碍和受损的线粒体自噬进一步形成氧化应激和炎症的有害反馈循环。尽管进行了广泛研究，但能够同时靶向NLRP3炎性小体激活和受损线粒体自噬的药物仍然稀缺。

方法

我们利用全面的细胞和动物模型探索了从九头狮子草中分离出的新型天然化合物纤毛喜树苷A（CA）的治疗潜力。在脂多糖/尼日利亚菌素（LPS/Nig）刺激的BV-2小胶质细胞中，评估了CA对炎性小体激活、细胞焦亡、线粒体健康和氧化应激的影响。使用蛋白质免疫印迹法、免疫荧光法和先进的线粒体自噬检测方法进行机制评估。此外，在表达人淀粉样β蛋白（Aβ）的秀丽隐杆线虫（C. elegans）模型和成熟的3xTg-AD小鼠模型中验证了CA的疗效。

结果

我们的结果表明，CA有效抑制BV-2细胞中NLRP3炎性小体的激活，减少小胶质细胞焦亡，并减轻氧化应激诱导的线粒体损伤。值得注意的是，我们确定AMPK/ULK1和PINK1/Parkin途径是CA强力激活线粒体自噬的新靶点。在体内观察到一致的治疗效果，CA显著减少Aβ诱导的麻痹、活性氧生成，并增强线虫的自噬。在3xTg-AD小鼠中，CA显著改善认知功能，减少Aβ斑块沉积，减轻神经炎症，并保持神经元完整性。