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

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

  • Phytomedicine. 2025 Feb 13:139:156502. doi: 10.1016/j.phymed.2025.156502.
Weipin Weng 1,  Baoping Lin 2,  Jiahao Zheng 1,  Yixin Sun 1,  Zijing Li 3,  Xiaochun Chen 4,  Yanping Wang 5,  Xiaodong Pan 6
Affiliations

Affiliations

  • 1 Department of Neurology, Center for Cognitive Neurology, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China; Institute of Clinical Neurology, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China.
  • 2 Department of Neurology, The First Affiliated Hospital of Yangtze University, Jingzhou, China.
  • 3 Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
  • 4 Department of Neurology, Center for Cognitive Neurology, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China; Institute of Clinical Neurology, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China. Electronic address: chenxc998@fjmu.edu.cn.
  • 5 Department of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, China. Electronic address: yp1014wang@163.com.
  • 6 Department of Neurology, Center for Cognitive Neurology, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China; Institute of Clinical Neurology, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China. Electronic address: pxd77316@163.com.
PMID: 39970860 DOI: 10.1016/j.phymed.2025.156502
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.

Keywords

Alzheimer's disease; Cycloastragenol; Microglia; PDE4B/CREB/BDNF pathway; Single-nuclei RNA sequencing.

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