Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Increasing evidence suggests that the gut–brain axis plays an important role in the pathogenesis of AD by linking intestinal homeostasis, gut microbiota, and brain metabolic regulation. Ginsenosides, the major bioactive components of Panax ginseng, possess diverse pharmacological activities including anti-inflammatory, antioxidant, and neuroprotective effects. However, the mechanisms by which ginsenosides alleviate AD-related cognitive impairment through the gut–brain axis remain incompletely understood. This study provides a systematic investigation of the neuroprotective effects of ginsenosides and the underlying mechanisms through integrated cellular models, animal studies, and multi-omics analyses. The protective effects of ginsenosides Rg1 and Rg2 were evaluated in SH-SY5Y neuroblastoma cells overexpressing Aβ(1–42). The results showed that both Rg1 and Rg2 activated autophagy, promoted the clearance of Aβ(1–42), and significantly reduced intracellular oxidative stress, suggesting that ginsenosides may alleviate Aβ-induced cytotoxicity through the regulation of autophagy-related pathways. The effects of ginsenosides Rb1 and Rb2 on cholesterol homeostasis were also evaluated in HepG2 cells. Both ginsenosides reduced intracellular cholesterol levels by modulating the SREBP-2–HMGCR and LXR-IDOL signaling pathways, and promoted the expression of mediators involved in cholesterol efflux and catabolism, suggesting a potential role of ginsenosides in regulating lipid metabolic processes associated with AD. To further explore the potential involvement of the gut–brain axis, network pharmacology analysis was performed to predict the key targets and signaling pathways associated with ginsenosides Rg2, Rb2, and compound K (CK) and AD. These predictions were subsequently validated in an intestinal epithelial injury model using Caco-2 cells. Ginsenoside treatment significantly increased TEER, reduced FITC-dextran permeability, upregulated tight junction proteins, and activate PI3K/AKT signaling pathway, indicating an improvement in intestinal barrier integrity. In the animal study, 3xTg-AD mice were used to evaluate the effects of ginsenosides Rg2, Rb2, and CK on AD-related phenotypes. Behavioral tests demonstrated that ginsenoside treatment significantly improved learning and memory abilities in AD mice. Moreover, ginsenosides reduced neuroinflammation and Aβ deposition in brain tissue. Gut microbiota analysis revealed that ginsenoside intervention reshaped the intestinal microbial community and influenced the production of short-chain fatty acids (SCFAs), suggesting a regulatory effect on gut microbial metabolism. Untargeted metabolomics analysis of brain tissue further showed that ginsenoside treatment partially corrected metabolic disturbances associated with energy metabolism, central carbon metabolism, and amino acid metabolism in 3xTg-AD mice. Correlation analyses revealed significant associations between key differential metabolites, gut microbial genera, SCFAs, inflammatory markers, and behavioral indicators, implying potential metabolic interactions along the gut–brain axis. Comparative analysis of different ginsenosides suggested distinct regulatory characteristics: Rg2 may primarily enhance mitochondrial energy metabolism and TCA cycle-related pathways, Rb2 may alleviate metabolic stress and energy imbalance, whereas CK appears to exert stronger effects on neurotransmitter regulation and neuroinflammatory responses. Overall, this study systematically elucidates the potential mechanisms by which ginsenosides improve AD-related cognitive impairment through the coordinated regulation of neuronal autophagy, cholesterol homeostasis, intestinal barrier integrity, gut microbiota composition, and brain metabolic networks. These findings provide new insights into the multifaceted neuroprotective effects of ginsenosides and highlight the gut–brain axis and metabolic regulation as promising targets for natural product-based interventions in Alzheimer’s disease.
Mechanistic Study of Ginsenosides in Ameliorating Alzheimer’s Disease Through Modulation of the Gut–Brain Axis
LIU, ZIQI
2026-06-16
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Increasing evidence suggests that the gut–brain axis plays an important role in the pathogenesis of AD by linking intestinal homeostasis, gut microbiota, and brain metabolic regulation. Ginsenosides, the major bioactive components of Panax ginseng, possess diverse pharmacological activities including anti-inflammatory, antioxidant, and neuroprotective effects. However, the mechanisms by which ginsenosides alleviate AD-related cognitive impairment through the gut–brain axis remain incompletely understood. This study provides a systematic investigation of the neuroprotective effects of ginsenosides and the underlying mechanisms through integrated cellular models, animal studies, and multi-omics analyses. The protective effects of ginsenosides Rg1 and Rg2 were evaluated in SH-SY5Y neuroblastoma cells overexpressing Aβ(1–42). The results showed that both Rg1 and Rg2 activated autophagy, promoted the clearance of Aβ(1–42), and significantly reduced intracellular oxidative stress, suggesting that ginsenosides may alleviate Aβ-induced cytotoxicity through the regulation of autophagy-related pathways. The effects of ginsenosides Rb1 and Rb2 on cholesterol homeostasis were also evaluated in HepG2 cells. Both ginsenosides reduced intracellular cholesterol levels by modulating the SREBP-2–HMGCR and LXR-IDOL signaling pathways, and promoted the expression of mediators involved in cholesterol efflux and catabolism, suggesting a potential role of ginsenosides in regulating lipid metabolic processes associated with AD. To further explore the potential involvement of the gut–brain axis, network pharmacology analysis was performed to predict the key targets and signaling pathways associated with ginsenosides Rg2, Rb2, and compound K (CK) and AD. These predictions were subsequently validated in an intestinal epithelial injury model using Caco-2 cells. Ginsenoside treatment significantly increased TEER, reduced FITC-dextran permeability, upregulated tight junction proteins, and activate PI3K/AKT signaling pathway, indicating an improvement in intestinal barrier integrity. In the animal study, 3xTg-AD mice were used to evaluate the effects of ginsenosides Rg2, Rb2, and CK on AD-related phenotypes. Behavioral tests demonstrated that ginsenoside treatment significantly improved learning and memory abilities in AD mice. Moreover, ginsenosides reduced neuroinflammation and Aβ deposition in brain tissue. Gut microbiota analysis revealed that ginsenoside intervention reshaped the intestinal microbial community and influenced the production of short-chain fatty acids (SCFAs), suggesting a regulatory effect on gut microbial metabolism. Untargeted metabolomics analysis of brain tissue further showed that ginsenoside treatment partially corrected metabolic disturbances associated with energy metabolism, central carbon metabolism, and amino acid metabolism in 3xTg-AD mice. Correlation analyses revealed significant associations between key differential metabolites, gut microbial genera, SCFAs, inflammatory markers, and behavioral indicators, implying potential metabolic interactions along the gut–brain axis. Comparative analysis of different ginsenosides suggested distinct regulatory characteristics: Rg2 may primarily enhance mitochondrial energy metabolism and TCA cycle-related pathways, Rb2 may alleviate metabolic stress and energy imbalance, whereas CK appears to exert stronger effects on neurotransmitter regulation and neuroinflammatory responses. Overall, this study systematically elucidates the potential mechanisms by which ginsenosides improve AD-related cognitive impairment through the coordinated regulation of neuronal autophagy, cholesterol homeostasis, intestinal barrier integrity, gut microbiota composition, and brain metabolic networks. These findings provide new insights into the multifaceted neuroprotective effects of ginsenosides and highlight the gut–brain axis and metabolic regulation as promising targets for natural product-based interventions in Alzheimer’s disease.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
