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. 2025 Feb 24:16:1528590.
doi: 10.3389/fphar.2025.1528590. eCollection 2025.

Ginsenoside Ro ameliorates cognitive impairment and neuroinflammation in APP/PS1 mice via the IBA1/GFAP-MAPK signaling pathway

Tianyao Li  1 , Jiaxin Chen  1 , Zhouyuan Xie  1 , Jiansong Fang  1 , Qiqing Wu  1 , Xinyue Cao  1 , Ziying Chen  1 , Yiyun Wang  1 , Qiqi Fan  2 , Qi Wang  1 , Jinman Liu  1   2
Affiliations

Ginsenoside Ro ameliorates cognitive impairment and neuroinflammation in APP/PS1 mice via the IBA1/GFAP-MAPK signaling pathway

Tianyao Li et al. Front Pharmacol. .

Abstract

Introduction: Ginseng, known as the "king of herbs," has long been used in traditional Chinese medicine due to its beneficial properties, including anti-aging, anti-inflammatory, and anti-apoptotic effects. Ginsenosides, the active compounds in ginseng, have shown promise in treating neurodegenerative diseases such as Alzheimer's disease (AD). This study investigates the therapeutic potential of Ginsenoside Ro and its underlying mechanisms in AD treatment.

Methods: In this study, male APP/PS1 transgenic mice were divided into five groups and treated with Ginsenoside Ro or ginseng for one month. Cognitive function and anxiety were assessed through behavioral tests, including the open field test (OFT) and Morris water maze (MWM). To evaluate Aβ deposition, neuronal apoptosis, neuroinflammation, and the MAPK pathway, various techniques were employed: Thioflavin-T staining, Nissl staining, immunofluorescence, Western blot, and qRT-PCR analyses.

Results: Ginsenoside Ro significantly improved cognitive function and reduced anxiety in APP/PS1 mice. It also decreased Aβ deposition and ameliorated neuronal apoptosis in the cerebral cortex. The treatment regulated the expression of pro-apoptotic proteins (Bax and Caspase3) and increased the anti-apoptotic protein Bcl-2. Additionally, Ginsenoside Ro reduced neuroinflammation by decreasing IBA1-positive microglia and GFAP-positive astrocytes and lowering pro-inflammatory cytokines while enhancing anti-inflammatory cytokine IL-10. Furthermore, the phosphorylation levels of p38 and JNK in the MAPK pathway were significantly reduced, suggesting a key mechanism for its therapeutic effects.

Discussion: These findings provide strong evidence supporting Ginsenoside Ro as a potential therapeutic agent for Alzheimer's disease. Its effects appear to be mediated through the modulation of the IBA1/GFAP-MAPK pathway, which may offer new insights into AD treatment strategies.

Keywords: APP/PS1 mice; Alzheimer’s disease; Ginsenoside Ro; IBA1/GFAP-MAPK pathway; neuroinflammation; neuronal apoptosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The whole process of mouse breeding and treatment.
FIGURE 2
FIGURE 2
HPLC fingerprint analysis of Ginsenoside Ro in ginseng.
FIGURE 3
FIGURE 3
Ginsenoside Ro improve spatial exploration ability and anxiety state in APP/PS1 mice. (A) Chemical structural formula of Ginsenoside Ro. (B) Diagram of open field trajectory. (C) Total distance traveled for locomotion. (D) Central residence time. (E) Mean speed. (F) Number of center entries. Data are expressed as MEAN ± SEM. Statistical significance is indicated as *P < 0.05, **P < 0.01, ***P < 0.001 (n = 6).
FIGURE 4
FIGURE 4
Ginsenoside Ro improves memory and cognitive impairment in APP/PS1 mice. (A) Water maze movement trajectory diagram. (B) Escape latency. (C) Number of platform crossings. (D) Time spent in target quadrant. Data are expressed as MEAN ± SEM, and statistical significance is indicated as *P < 0.05, **P < 0.01, ***P < 0.001 (n = 6).
FIGURE 5
FIGURE 5
RT q-PCR results of Ginsenoside Ro to modulate the expression of AD-related targets. (A) q-PCR results of MAPK8. (B) q-PCR results of MAPK9. (C) q-PCR results of CDK28. (D) q-PCR results of BACE1. (E) q-PCR results of FLT1. (F) q-PCR results of CCR5. Data are expressed as MEAN ± SEM, and statistical significance is indicated as *P < 0.05, **P < 0.01, ***P < 0.001, (n = 3).
FIGURE 6
FIGURE 6
Ginsenoside Ro reduce Aβ deposition and ameliorate neuronal apoptosis in the cerebral cortex of APP/PS1 mice. (A) Representative image of thioflavin-T staining fluorescence. (B) Histogram of thioflavin-T fluorescence statistics. (C) Representative image of Nissl staining in the mouse hippocampal area. (D) Histogram of cell counts in the CA1 region. (E) Histogram of cell counts in the CA3 region. (F) Histogram of cell counts in the DG region. (G) Representative graph of fluorescence of TUNEL staining. (H) Histogram of fluorescence statistics of TUNEL staining.Data are expressed as MEAN ± SEM. Statistical significance is indicated as *P < 0.05, **P < 0.01, ***P < 0.001 (n = 3).
FIGURE 7
FIGURE 7
Ginsenoside Ro modulates neuronal apoptosis in APP/PS1 mice. (A) Representative images of immunofluorescence staining for Bax, Bcl-2, and Caspase3. (B) Histogram of immunofluorescence intensity for Bax. (C) Histogram of immunofluorescence intensity for Bcl-2. (D) Histogram of immunofluorescence intensity for Caspase3. (E) Representative Western blot images for Bax, Bcl-2, and Caspase3. (F) Histogram of Western blot data for Bax. (G) Histogram of Western blot data for Bcl-2. (H) Histogram of Western blot data for Caspase3. Data are expressed as MEAN ± SEM, with statistical significance indicated as *P < 0.05, **P < 0.01, ***P < 0.001 (n = 3).
FIGURE 8
FIGURE 8
Ginsenoside Ro ameliorates neuroinflammation in the brains of APP/PS1 mice. (A) Representative images of IBA1 and GFAP immunofluorescence. (B) Histogram of cell activation statistics for IBA1 microglia. (C) Histogram of GFAP astrocyte activation statistics. (D) Representative images of Western blot for IBA1 and GFAP. (E) Histogram of Western blot statistics for IBA1. (F) Histogram of Western blot statistics for GFAP. (G) Histogram of q-PCR results for TNFα. (H) Histogram of q-PCR results for IL-1β. (I) Histogram of q-PCR results for IL-6. (J) Histogram of q-PCR results for the anti-inflammatory indicator IL-10. Data are expressed as MEAN ± SEM, with statistical significance indicated as *P < 0.05, **P < 0.01, ***P < 0.001 (n = 3).
FIGURE 9
FIGURE 9
Mechanism of the effect of Ginsenoside Ro on the MAPK pathway in APP/PS1 mice. (A) Representative images of Western blot for p-p38, p-ERK, and p-JNK. (B) Histogram of Western blot statistics for p38. (C) Histogram of Western blot statistics for ERK. (D) Histogram of Western blot statistics for JNK. (E) Histogram of Western blot statistics for p-p38/p38. (F) Histogram of Western blot statistics for p-ERK/ERK. (G) Histogram of Western blot statistics for p-JNK/JNK. Data are expressed as MEAN ± SEM, and statistical significance is expressed as *P < 0.05, **P < 0.01, ***P < 0.001 (n = 3)
FIGURE 10
FIGURE 10
Potential mechanisms of Ginsenoside Ro in the treatment of AD.
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