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Trilobatin rescues cognitive impairment of Alzheimer’s disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cognitive impairment that currently is uncurable. Previous study shows that trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect in experimental models of AD. In the present study we investigated the molecular mechanisms underlying the beneficial effect of TLB on experimental models of AD in vivo and in vitro. APP/PS1 transgenic mice were administered TLB (4, 8 mg· kg−1 ·d−1, i.g.) for 3 months; rats were subjected to ICV injection of Aβ25-35, followed by administration of TLB (2.5, 5, 10 mg· kg−1 ·d−1, i.g.) for 14 days. We showed that TLB administration significantly and dose-dependently ameliorated the cognitive deficits in the two AD animal models, assessed in open field test, novel object recognition test, Y-maze test and Morris water maze test. Furthermore, TLB administration dose-dependently inhibited microglia and astrocyte activation in the hippocampus of APP/PS1 transgenic mice accompanied by decreased expression of high-mobility group box 1 (HMGB1), TLR4 and NF-κB. In Aβ25-25-treated BV2 cells, TLB (12.5−50 μM) concentration-dependently increased the cell viability through inhibiting HMGB1/TLR4/NF-κB signaling pathway. HMGB1 overexpression abrogated the beneficial effects of TLB on BV2 cells after Aβ25-35 insults. Molecular docking and surface plasmon resonance assay revealed that TLB directly bound to HMGB1 with a KD value of 8.541×10−4 M. Furthermore, we demonstrated that TLB inhibited Aβ25-35-induced acetylation of HMGB1 through activating SIRT3/SOD2 signaling pathway, thereby restoring redox homeostasis and suppressing neuroinflammation. These results, for the first time, unravel a new property of TLB: rescuing cognitive impairment of AD via targeting HMGB1 and activating SIRT3/SOD2 signaling pathway.

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Fig. 1: TLB rescued cognitive impairement and Aβ burden in APP/PS1 mice.
Fig. 2: Effect of TLB on activation of microglia and astrocytes through HMGB1/TLR4/NF-κB signaling pathway in hippocampus of APP/PS1 mice.
Fig. 3: Effects of TLB on redox status in the APP/PS1 mice.
Fig. 4: TLB directly bound to HMGB1.
Fig. 5: TLB inhibits Aβ25-35-induced cytotoxicity in BV2 cells via targeting HMGB1 through SIRT3/SOD2/mtROS signaling pathway.
Fig. 6: Reciprocity between HMGB1 and SIRT3 was involved in the neuroprotective effects of TLB on cognitive impairment of AD.
Fig. 7: Schematic depicting the role of TLB on AD.

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Acknowledgements

This work was supported by Science and Technology Support Plan of Guizhou Province (No. [2020]1Y010), Innovative Research Team of comprehensive utilization with Lithocarpus polystachyus Rehd. sweet tea in Zunyi City (No. [2021]4), Zunyi Science and Technology Project (No. [2021]187), Program for Changjiang Scholars and Innovative Research Team in University, China (No. IRT_17R113).

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JMG, GTS, XZ, NNC, YGL, and YW performed the experiments. FX and YQH helped with bioinformatics analysis and molecular docking analysis. JYZ and FL helped with LC-MS analysis. All authors were involved in the analysis of data. JMG wrote the manuscript. JSS and QHG designed the experiments and revised the manuscript.

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Correspondence to Qi-hai Gong.

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Gao, Jm., Zhang, X., Shu, Gt. et al. Trilobatin rescues cognitive impairment of Alzheimer’s disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway. Acta Pharmacol Sin 43, 2482–2494 (2022). https://doi.org/10.1038/s41401-022-00888-5

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  • DOI: https://doi.org/10.1038/s41401-022-00888-5

Keywords

  • trilobatin
  • Alzheimer’s disease
  • 25-35
  • HMGB1
  • neuroinflammation
  • oxidative stress

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