Scopoletin alleviates cognitive deficits in 5xFAD mice via suppressing microglial inflammatory response.

Abstract

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.