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

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.