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

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

doi:10.1186/s12967-023-04137-z

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

J Transl Med. 2023 Apr 24;21(1):277. doi: 10.1186/s12967-023-04137-z.

Authors

Yuqing Liu^#^{1

2}, Hongli Li^#^{1

2}, Xiaowei Wang³, Jianhua Huang⁴, Di Zhao⁴, Yejun Tan⁵, Zheyu Zhang^{1

2}, Zhen Zhang⁶, Lemei Zhu⁷, Beibei Wu^{1

2}, Zhibao Chen^{1

2}, Weijun Peng^{8

9}

Affiliations

¹ Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
² National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
³ Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
⁴ Hunan Academy of Chinese Medicine, Changsha, 410013, People's Republic of China.
⁵ School of Mathematics, University of Minnesota Twin Cities, Minneapolis, MN, 55455, USA.
⁶ YangSheng College of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China.
⁷ Academician Workstation, Changsha Medical University, Changsha, 410219, China.
⁸ Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China. pengweijun87@csu.edu.cn.
⁹ National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China. pengweijun87@csu.edu.cn.

^# Contributed equally.

Abstract

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.

Keywords: APP/PS1 mice; Akkermansia; Alistipe; Alzheimer’s disease (AD); Icariin (ICA); Network pharmacology (NP); Sphingolipid metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease*
Animals
Gastrointestinal Microbiome*
Mice
Mice, Transgenic
Network Pharmacology
RNA, Ribosomal, 16S

Substances

icariin
RNA, Ribosomal, 16S