Renshen Shouwu formula alleviates Alzheimer's disease pathology by modulating tryptophan metabolism and activating the SIRT1 signaling pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: The Renshen Shouwu is a traditional Chinese medicine formula, whose active components have neuroprotective and multiple pharmacological effects. However, Alzheimer's disease (AD) is a complex neurodegenerative disorder, and the exact mechanism of its treating AD remains to be elucidated, and more in - depth research is needed. AIM OF THE STUDY: The aim of this study is to elucidate the protective effect and potential molecular mechanisms of Renshen Shouwu Formula (RSSW) on AD. MATERIALS AND METHODS: Using senescence-accelerated mouse prone 8 (SAMP8) mice as an AD model, the cerebral cortex morphology was assessed by H&E staining. Non-targeted and targeted metabolomics, together with 16S rRNA sequencing, were performed to analyze the effects of RSSW on metabolic changes and gut microbiota in SAMP8 mice. Furthermore, potential therapeutic targets of RSSW were predicted by network pharmacology and validated via Western blot. RESULTS: RSSW treatment significantly mitigated pathological damage in the cerebral cortex, and reduced pro-inflammatory cytokine levels in SAMP8 mice. Results of both non-targeted and targeted metabolomics analyses indicated that RSSW intervention could improve tryptophan metabolism in SAMP8 mice by elevating tryptophan levels, suppressing kynurenine pathway overactivation, and enhancing serotonin and indole derivative biosynthesis. Additionally, RSSW administration markedly increased the relative abundance of Lactobacillus in gut microbiota, which showed positive correlations with the levels of tryptophan, serotonin pathway metabolites, and neurotransmitters, and negatively with kynurenine pathway metabolites. Furthermore, network pharmacology identified that SIRT1 could serve as a potential target for RSSW in AD. Notably, RSSW upregulated SIRT1 protein levels and reduced levels of Ac-p53 and acetylated NF-κB proteins in the hippocampus of SAMP8 mice. CONCLUSIONS: RSSW suppresses the progression of AD by regulating tryptophan metabolism, reshaping the gut microbiota, and activating SIRT1-mediated signaling pathways. These findings suggest that RSSW may be a promising therapeutic strategy for AD through multi-path action mechanisms.