Scopoletin alleviates cognitive deficits in 5xFAD mice via suppressing microglial inflammatory response
Xiaoyan Ouyang1, Zhenzhen Zhao1, Yifei Hou1
1The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Background:
Microglia-driven inflammation is a key pathological hallmark of Alzheimer's disease (AD). Scopoletin is a natural coumarin compound from Erycibe obtusifolia Benth with anti-inflammatory activity. However, its effects on microglial inflammatory response and cognition in AD models need to be defined.
Purpose:
To evaluate the pharmacological effects of scopoletin on microglial inflammatory response and cognitive improvement in 5xFAD models.
Methods:
Anti-inflammatory effects were assessed in LPS-stimulated BV2 and primary microglia and LPS-induced inflammation in vivo model by measuring cytokines, inflammatory markers. In 5xFAD mice, inflammation, Aβ burden, and cognitive behavior were examined. RNA sequencing, siRNA knockdown, and western blot were performed to determine inflammatory regulation pathways.
Results:
Scopoletin significantly reduced IL-6 and TNF-α and reversed M1/M2 polarization in LPS-stimulated BV2, suppressed microglial morphological changes in primary microglia, and attenuated LPS-induced inflammation in vivo. Scopoletin treatment alleviated inflammation and reduced Aβ deposition in the hippocampus and cortex, and improved cognitive impairment in 5xFAD mice. Furthermore, transcriptomic signature analyses suggest that scopoletin could modulate inflammatory signaling pathways in LPS-stimulated BV2 cells by elevating downstream mediators, such as Topoisomerase II Alpha (Top2A) and PP2A-NF-κB signaling.
Conclusion:
Scopoletin suppressed microglial inflammatory response and improved cognitive impairment in 5xFAD mice, providing new insight into new leading compound for AD modifying therapy.
Insights
Scopoletin, an anti-inflammatory compound, reduced neuroinflammation and improved cognitive function in Alzheimer's disease (AD) models. This study highlights its potential as a therapeutic agent for AD by targeting microglial activation.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Microglia-driven inflammation is central to Alzheimer's disease (AD) pathology.
- Scopoletin, a natural coumarin, exhibits anti-inflammatory properties.
- The therapeutic potential of scopoletin in AD models remains largely undefined.
Purpose of the Study:
- To investigate the pharmacological effects of scopoletin on microglial inflammatory responses.
- To evaluate scopoletin's efficacy in improving cognitive function in 5xFAD mouse models of AD.
Main Methods:
- Assessed anti-inflammatory effects in LPS-stimulated BV2 and primary microglia.
- Evaluated in vivo inflammation, amyloid-beta (Aβ) burden, and cognitive behavior in 5xFAD mice.
- Utilized RNA sequencing, siRNA knockdown, and western blot to elucidate regulatory pathways.
Main Results:
- Scopoletin significantly reduced pro-inflammatory cytokines (IL-6, TNF-α) and modulated microglial polarization.
- In 5xFAD mice, scopoletin alleviated neuroinflammation, decreased Aβ deposition, and improved cognitive deficits.
- Transcriptomic analysis indicated scopoletin modulates inflammatory signaling via Top2A and PP2A-NF-κB pathways.
Conclusions:
- Scopoletin effectively suppresses microglial inflammation and ameliorates cognitive impairment in AD models.
- These findings suggest scopoletin as a promising lead compound for AD-modifying therapies.
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