Effects of Hesperetin Early Intervention on Brain Neurons and Microglia in APPswe/PS1dE9 Mice
Nan Wang1, Hao Wen2, Ying Sun2
1Institute of Chinese Materia Medica, Chengde Medical University, Chengde, 067000, PR China, Tianjin Occupational Diseases Precaution and Therapeutic Hospital, Tianjin, 300000, PR China.
Introduction:
Neuroinflammation and microglial dysfunction play central roles in the pathogenesis of Alzheimer's disease (AD). This study investigated whether early intervention with hesperetin, a citrus flavonoid, could attenuate neuroinflammation and modulate microglial polarization in both wild-type (WT) and APPswe/PS1dE9 transgenic (TG) mice.
Methods:
Three-month-old male C57BL/6J WT and APPswe/PS1dE9 TG mice were administered hesperetin (10 or 20 mg/kg/day for WT; 20, 40, or 80 mg/kg/day for TG) or vehicle for six months. Neuronal morphology was assessed using thionine staining. Microglial polarization was evaluated via CD11b/iNOS and CD11b/Arginase-1 immunofluorescence. Protein expression of CD11b, iNOS, Arginase-1, and TREM2 was measured by Western blot, and cytokine levels (TNF-α, IL-10) were quantified by ELISA.
Results:
In WT mice, hesperetin improved neuronal integrity, reduced M1 markers (CD11b⁺/ iNOS⁺ cells, iNOS, TNF-α), and enhanced M2 markers (CD11b⁺/Arginase-1⁺ cells, Arginase-1, TREM2). TG mice exhibited exacerbated neuroinflammation and neuronal loss compared to WT controls, which was significantly mitigated by hesperetin treatment. All hesperetin doses in TG groups reduced pro-inflammatory markers and increased anti-inflammatory and repair-associated factors.
Discussion:
These results indicate that hesperetin shifts microglial polarization toward the protective M2 phenotype, potentially via TREM2 upregulation, thereby reducing neuroinflammation and neuronal damage. This effect was observed in both age-related and Aβ-driven pathology, suggesting a dual role for hesperetin in immunomodulation and neuroprotection.
Conclusion:
Early hesperetin intervention exerts neuroprotective effects by rebalancing microglial polarization and enhancing TREM2 expression, highlighting its potential as a preventive strategy against AD-related neuroinflammation.
Insights
Hesperetin, a citrus flavonoid, reduces neuroinflammation and neuronal damage in Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Neuroinflammation and microglial dysfunction are key factors in Alzheimer's disease (AD) pathogenesis.
- Investigating early interventions for AD is crucial for developing effective treatment strategies.
Purpose of the Study:
- To determine if hesperetin, a citrus flavonoid, can reduce neuroinflammation and alter microglial polarization.
- To assess hesperetin's effects in both wild-type (WT) and APPswe/PS1dE9 transgenic (TG) mouse models of AD.
Main Methods:
- WT and TG mice were treated with hesperetin or vehicle for six months.
- Neuronal morphology, microglial polarization (M1/M2 markers), protein expression (CD11b, iNOS, Arginase-1, TREM2), and cytokine levels (TNF-α, IL-10) were analyzed.
Main Results:
- Hesperetin improved neuronal integrity and reduced M1 markers (pro-inflammatory) while increasing M2 markers (anti-inflammatory and repair) in WT mice.
- Hesperetin treatment significantly mitigated neuroinflammation and neuronal loss in TG mice.
- All hesperetin doses in TG groups reduced pro-inflammatory markers and increased anti-inflammatory/repair factors.
Conclusions:
- Hesperetin promotes a shift towards the protective M2 microglial phenotype, potentially through TREM2 upregulation.
- Hesperetin demonstrates immunomodulatory and neuroprotective effects, reducing neuroinflammation and neuronal damage.
- Early hesperetin intervention shows potential as a preventive strategy for AD-related neuroinflammation.
