Journal Article

Anti-Alzheimers molecular mechanism of icariin: insights from gut microbiota, metabolomics, and network pharmacology

Zhang, Zheyu, Liu, Yuqing, Wu, Beibei, Chen, Zhibao, Huang, Jianhua, Zhang, Zhen, Li, Hongli, Wang, Xiaowei, Tan, Yejun, Zhu, Lemei, Peng, Weijun, Zhao, Di

2023

Overview

Background Icariin (ICA), an active ingredient extracted from Epimedium species, has shown promising results in the treatment of Alzheimer's disease (AD), although its potential therapeutic mechanism remains largely unknown. This study aimed to investigate the therapeutic effects and the underlying mechanisms of ICA on AD by an integrated analysis of gut microbiota, metabolomics, and network pharmacology (NP). Methods The cognitive impairment of mice was measured using the Morris Water Maze test and the pathological changes were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in the gut microbiota and fecal/serum metabolism. Meanwhile, NP was used to determine the putative molecular regulation mechanism of ICA in AD treatment. Results Our results revealed that ICA intervention significantly improved cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of the APP/PS1 mice. Moreover, the gut microbiota analysis showed that ICA administration reversed AD-induced gut microbiota dysbiosis in APP/PS1 mice by elevating the abundance of Akkermansia and reducing the abundance of Alistipe . Furthermore, the metabolomic analysis revealed that ICA reversed the AD-induced metabolic disorder via regulating the glycerophospholipid and sphingolipid metabolism, and correlation analysis revealed that glycerophospholipid and sphingolipid were closely related to Alistipe and Akkermansia . Moreover, NP indicated that ICA might regulate the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis for the treatment of AD. Conclusion These findings indicated that ICA may serve as a promising therapeutic approach for AD and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Akkermansia / AKT1 protein / Alistipe / Alzheimer Disease / Alzheimer's disease / Alzheimer’s disease (AD) / Animal cognition / Animals / APP/PS1 mice / Bioflavonoids / Biomedical and Life Sciences / Biomedicine / Care and treatment / Cognitive ability / Correlation analysis / Discriminant analysis / Dysbacteriosis / Feces / Flavones / Flavonoids / Gastrointestinal Microbiome / Genes / Gut microbiota / Health aspects / Icariin (ICA) / Intestinal microflora / Laboratory animals / Lipid metabolism / Medicine/Public Health / Memory / Metabolic disorders / Metabolism / Metabolites / Metabolomics / Mice / Mice, Transgenic / Microbiota / Molecular modelling / Network Pharmacology / Neurodegenerative diseases / Patient outcomes / Presenilin 1 / Proteins / RNA, Ribosomal, 16S / rRNA 16S / Signal transduction / Software / Sphingolipid metabolism / Translational Metagenomics / Tumor necrosis factor-TNF / Variance analysis