Integrated multi-omics analysis and experimental validation reveals the mechanism of tenuifoliside A activity in Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE

Alzheimer's disease (AD) is characterized by progressive cognitive dysfunction and memory loss. Tenuifoliside A (TFSA) is a constituent of RADIX POLYGALAE, a medicinal herb traditionally used in the clinical treatment of AD in China. However, the therapeutic mechanism of this compound is unknown.

AIM OF THE STUDY

To investigate the effects and pharmacological mechanisms of TFSA in ameliorating AD symptoms in APP/PS1 mice.

MATERIALS AND METHODS

The neuroprotective effects of TFSA were assessed using behavioral tests, transmission electron microscopy, and immunofluorescence staining. The differential metabolites in the feces of model mice were obtained from non-targeted metabolomics analysis. Differential abundances of microbiota in the gut were investigated by 16S rRNA sequencing, and correlations among differential metabolites and microbiota were investigated using an integrated approach.

RESULTS

Cognitive impairment and Aβ burden were mitigated in APP/PS1 mice treated with TFSA. TFSA intervention led to an increase in the diversity of gut microbiota and a reduction in the relative abundance of Firmicutes, Bacteroidetes, and Proteobacteria. There were 71 differential metabolites in mice given high dose of TFSA. In comparison to the AD group, the mice treated with TFSA exhibited a notable enrichment in various pathways including glucose and lipid metabolism, tryptophan metabolism. Based on integrated metabolomics and 16S rRNA sequencing, 23 metabolite-microbiota pairs were different between the TFSA and AD groups, and there was an especially strong correlation between Alistipes and 2,3-dinor-8-epi-prostaglandin F2α. Validation experiment demonstrated TFSA ameliorates AD by regulating metabolism pathways and inhibiting neuroinflammation.

CONCLUSIONS

This study offers a theoretical basis for elucidating the molecular mechanism of TFSA's amelioration of AD. Although the potential pharmacological mechanisms of TFSA are still unknown, we have demonstrated that TFSA inhibits neuroinflammation and improves AD symptoms in APP/PS1 mice by remodeling the microbiota and its metabolites.