Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Kaempferol attenuates microglial activation in Alzheimer's disease via inhibiting the cytosolic HK2-mediated NF-κB signaling pathway.
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Wang Mengyao, Guo Minsong, Li Simeng, Song Liyu, Wu Meihong, Zhao Jiahui, Xu Tengfei, Zhou Yuan
Аннотация
INTRODUCTION: Kaempferol (KAE), a natural flavonoid with substantial anti-inflammatory activity, has demonstrated efficacy against Alzheimer's disease (AD). However, the fundamental mechanisms are not yet fully understood.
OBJECTIVES: The objective of this study was to elucidate the role of KAE in alleviating microglia-mediated neuroinflammation in AD and its underlying mechanisms.
METHODS: The 3 × Tg-AD mice and LPS-stimulated BV2 microglial cells were employed as in vivo and in vitro model respectively. The HK-TAT peptide was utilized to induce mitochondrial dissociation of HK2, and 3-BP was applied as a HK2 inhibitor. Transcriptomic and metabolomic analyses were performed to discover the inhibitory effect of KAE on HK2. Immunofluorescence and Western blotting were employed to explore the suppressive role of KAE in cytosolic HK2-mediated NF-κB signaling. Additionally, the interaction between KAE and HK2 was investigated through molecular docking, validated by SPR, and confirmed via CETSA.
RESULTS: Our findings demonstrated that KAE significantly attenuated LPS-induced microglial activation, along with the release of pro-inflammatory factors and enhanced glycolytic activity. In vivo, KAE partially rescued cognitive impairment and neuronal damage in 3 × Tg-AD mice. Microglial activation was also markedly suppressed. Mechanistically, we revealed that dissociation of HK2 from mitochondria to the cytosol was sufficient to induce microglial activation, and this process was consequently constrained by the suppression of HK2 level and activity using 3-BP. By reducing HK2 levels, KAE suppressed cytosolic HK2-mediated IκBα phosphorylation and subsequent nuclear translocation of NF-κB. Furthermore, KAE not only downregulated HK2 transcription but also bound to HK2, promoting its ubiquitination-mediated degradation.
CONCLUSION: Our data indicate that KAE alleviates microglia-mediated neuroinflammation in AD, which correlates with the suppression of HK2 and the modulation of cytosolic HK2-dependent NF-κB activation.
OBJECTIVES: The objective of this study was to elucidate the role of KAE in alleviating microglia-mediated neuroinflammation in AD and its underlying mechanisms.
METHODS: The 3 × Tg-AD mice and LPS-stimulated BV2 microglial cells were employed as in vivo and in vitro model respectively. The HK-TAT peptide was utilized to induce mitochondrial dissociation of HK2, and 3-BP was applied as a HK2 inhibitor. Transcriptomic and metabolomic analyses were performed to discover the inhibitory effect of KAE on HK2. Immunofluorescence and Western blotting were employed to explore the suppressive role of KAE in cytosolic HK2-mediated NF-κB signaling. Additionally, the interaction between KAE and HK2 was investigated through molecular docking, validated by SPR, and confirmed via CETSA.
RESULTS: Our findings demonstrated that KAE significantly attenuated LPS-induced microglial activation, along with the release of pro-inflammatory factors and enhanced glycolytic activity. In vivo, KAE partially rescued cognitive impairment and neuronal damage in 3 × Tg-AD mice. Microglial activation was also markedly suppressed. Mechanistically, we revealed that dissociation of HK2 from mitochondria to the cytosol was sufficient to induce microglial activation, and this process was consequently constrained by the suppression of HK2 level and activity using 3-BP. By reducing HK2 levels, KAE suppressed cytosolic HK2-mediated IκBα phosphorylation and subsequent nuclear translocation of NF-κB. Furthermore, KAE not only downregulated HK2 transcription but also bound to HK2, promoting its ubiquitination-mediated degradation.
CONCLUSION: Our data indicate that KAE alleviates microglia-mediated neuroinflammation in AD, which correlates with the suppression of HK2 and the modulation of cytosolic HK2-dependent NF-κB activation.