Novel application of cycloastragenol target microglia for the treatment of Alzheimer's disease: Evidence from single-cell analysis, network pharmacology and experimental assessment

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-02-13 DOI:10.1016/j.phymed.2025.156502

Weipin Weng , Baoping Lin , Jiahao Zheng , Yixin Sun , Zijing Li , Xiaochun Chen , Yanping Wang , Xiaodong Pan

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引用次数: 0

Abstract

Background

Cycloastragenol (CAG), a compound extracted from Astragalus, is known for its telomerase activation and anti-inflammatory, antioxidant properties. However, its potential pharmacological effects on Alzheimer's disease (AD) remain unclear.

Purpose

This study aimed to explore potential targets and molecular mechanisms for the role of CAG in alzheimer’s disease (AD) treatment.

Methods

CAG was administered to 5 × FAD mice. The senescent cell count was verified by senescence-associated β-galactosidase (SA-β-gal) staining. The impact of CAG on microglial phagocytosis was assessed by in vitro and in vivo assays. The potential targets of CAG were identified by network pharmacology and single-nucleus RNA sequencing (snRNA-seq). The underlying mechanism was validated by molecular docking, surface plasmon resonance (SPR) and western blotting.

Results

CAG effectively ameliorated cognitive impairments and microglial senescence in 5 × FAD mice. In vivo and in vitro experiments revealed that CAG modulated microglial phagocytic activity and reduced hippocampal Aβ deposition The analysis of single-nucleus RNA sequencing data of AD patients reported 13 microglial targets for AD intervention. Phosphodiesterase 4B (PDE4B) was identified as the target through which CAG regulated microglial activity by utilizing network pharmacology, molecular docking and SPR. Western blotting revealed that the PDE4B/CREB/BDNF pathway may mediate the regulatory effect of CAG.

Conclusion

CAG can enhance microglial phagocytosis and alleviate memory dysfunction and amyloid plaque pathology. Our findings suggest that CAG may regulate microglial function through its interaction with PDE4B, providing a novel therapeutic strategy for AD.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.