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

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. Graphical Abstract

Role of microbiota-gut-brain axis in natural aging-related alterations in behavior

“…In addition, aging induced the upregulation of LPS-producing bacterial such as Bacteroidaceae and Bacteroides , which are at lower abundance in young mice. It has been demonstrated that a high abundance of Alistipes , Bacteroides , Clostridium_sensu_stricto _1, Colidextribacter and Lachnoclostridium was associated with dysbiosis, oxidative stress, obesity, chronic inflammation and neurodegenerative diseases, indicating that these microbes may increase the risk of the onset of chronic diseases and inflammation ( Zafar and Saier, 2021 ; Cai et al, 2022 ; Pang et al, 2022 ; Liu et al, 2023 ; Yang et al, 2023 ).…”

Icariin prevents methylmercury-induced experimental neurotoxicity: Evidence from cerebrospinal fluid, blood plasma, brain samples, and in-silico investigations

“…Our research also seeks to establish whether SIRT-1, Nrf-2/HO-1, and MBP levels can be diagnostic markers for ALS. Through our research, we examined the phytoconstituent icariin, which has been utilized in the treatment of various neurodegenerative and neuropsychiatric disorders, including AD [ [67] , [68] , [69] , [70] , [71] ], Bipolar disorders [ 72 ], Ischemic Stroke [ 73 ], PD [ 14 ], and Schizophrenia [ 36 ].…”

Effect of Human Milk Oligosaccharides on Learning and Memory in Mice with Alzheimer’s Disease

“…This is similar to a recent study that reported that the Icariin intervention significantly improved cognitive dysfunction in AD mice by elevating the abundance of Akkermansia and reducing the abundance of Mucispirillum. As a recognized next-generation probiotic, Akkermansia is closely related to the positive systemic effects on host metabolism and homeostatic immunity and significantly contributes to the progression of AD. , Akkermansia has been found to enhance the reduction of Aβ40–42 and ameliorate intestinal barrier dysfunction . Previous studies have suggested that Clostridium butyricum regulates gut homeostasis and induces IL-10-producing macrophages and response in anti-inflammatory; thus, it is a breakthrough in probiotics …”