Liu Ying, Hong Ting, Lv Mingxuan, Guo Xiaoyu, Zhang Panpan, Yan Aijuan, Wei Wenshi
Department of Neurology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China.
Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, 200040, China.
Alzheimers Res Ther. 2025 Jun 20;17(1):138. doi: 10.1186/s13195-025-01783-x.
BACKGROUND: Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy. OBJECTIVES: This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms. METHODS: We employed APP/PS1 mice, naturally aged mice, and an in vitro model using Aβ42-induced senescent BV2 microglia. Delphinidin's effects were evaluated through assessments of cognitive function, synaptic integrity (synapse loss), Aβ plaque burden, senescent microglia gene signatures, and cellular senescence markers (including senescence-associated β-galactosidase activity, SASP factor expression, oxidative stress, and cyclin p21/p16 levels). Mechanistic studies involved analyzing the AMPK/SIRT1 signaling pathway, testing direct delphinidin-SIRT1 interaction, and using the AMPK inhibitor Compound C. RESULTS: Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, Aβ peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, cyclin p21 and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. In vitro, delphinidin treatment attenuated cell senescence induced by Aβ42 in BV2 microglia cells. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence. CONCLUSION: Our study reveals for the first time that delphinidin effectively improved cognitive deficits, alleviated synapse loss and Aβ pathology in APP/PS1 mice by mitigating microglial senescence. These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.
背景：新出现的证据表明，衰老的小胶质细胞在阿尔茨海默病（AD）的β-淀粉样蛋白（Aβ）病理和神经炎症中起作用。用细胞毒性最小的天然化合物靶向衰老细胞是一种有前景的治疗策略。 目的：本研究旨在探讨天然存在的花青素飞燕草素是否能通过减轻小胶质细胞衰老来缓解AD相关病理，并阐明其潜在的分子机制。 方法：我们使用了APP/PS1小鼠、自然衰老小鼠以及使用Aβ42诱导的衰老BV2小胶质细胞的体外模型。通过评估认知功能、突触完整性（突触丢失）、Aβ斑块负荷、衰老小胶质细胞基因特征以及细胞衰老标志物（包括衰老相关β-半乳糖苷酶活性、衰老相关分泌表型因子表达、氧化应激以及细胞周期蛋白p21/p16水平）来评估飞燕草素的作用。机制研究包括分析AMPK/SIRT1信号通路、检测飞燕草素与SIRT1的直接相互作用以及使用AMPK抑制剂化合物C。 结果：飞燕草素治疗通过下调衰老小胶质细胞基因特征，显著减轻了APP/PS1小鼠的认知缺陷、突触丢失和Aβ肽斑块，预防了细胞衰老，包括衰老相关β-半乳糖苷酶活性、衰老相关分泌表型（SASP）、氧化应激、细胞周期蛋白p21和p16。并且飞燕草素治疗还预防了自然衰老小鼠中的小胶质细胞衰老。在体外，飞燕草素治疗减轻了Aβ42在BV2小胶质细胞中诱导的细胞衰老。进一步研究表明，飞燕草素治疗增强了AMPK/SIRT1信号通路。此外，发现飞燕草素与SIRT1直接相互作用。值得注意的是，AMPK抑制剂化合物C逆转了飞燕草素对小胶质细胞衰老的保护作用。 结论：我们的研究首次揭示，飞燕草素通过减轻小胶质细胞衰老，有效改善了APP/PS1小鼠的认知缺陷，减轻了突触丢失和Aβ病理。这些发现突出了飞燕草素作为一种有前景的天然抗衰老剂，可对抗衰老及与年龄相关疾病的发展。
Biochim Biophys Acta Mol Basis Dis. 2025-8
Proc Natl Acad Sci U S A. 2024-4-30
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