Amentoflavone Ameliorates Memory Deficits and Abnormal Autophagy in Aβ25−35-Induced Mice by mTOR Signaling

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease in which autophagy plays a crucial role. Amentoflavone is a flavonoid obtained from various plants and has been shown to have AD-resistant neuroprotective effects. This study investigated the role of amentoflavone on memory impairment and abnormal autophagy in amyloid-β25–35 (Aβ25−35)-induced mice to elucidate the mechanisms by which it exerts neuroprotective effects. In this experiment, the AD mouse model was established by intracerebroventricular (ICV) injection of Aβ25−35 peptides, and amentoflavone was administered orally for 4 weeks. Behavioral changes in mice and pathological changes in the hippocampus were observed, and levels of inflammation, oxidative stress, and autophagy in the brain were detected and analyzed. PC-12 and APPswe-N2a cells were used in vitro to further investigate the effect of amentoflavone on the level of intracellular autophagy. Molecular docking was used to determine the action sites of amentoflavone. The results showed that amentoflavone improved memory function, eased anxiety symptoms in Aβ25−35-induced mice, and reduced atrophic degeneration of neurons in the hippocampus. Moreover, amentoflavone lessened the oxidative stress and inflammation in the brains of mice. Through in vivo and in vitro experiments, we found that amentoflavone may enhance autophagy, by way of binding to the ATP site of the mTOR protein kinase domain. Amentoflavone not only interacted with mTOR, but also improved Aβ25−35-induced cognitive dysfunction in mice by enhancing autophagy, attenuating levels of inflammation and oxidative stress, and reducing apoptosis in brain cells.

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Acknowledgements

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by the National Key Research and Development Project (2019YFC1708802, 2017YFC1702800), the Major Science and Technology Projects in Henan Province (171100310500), the Henan province high-level personnel special support “Zhong Yuan One Thousand People Plan” – Zhongyuan Leading Talent (ZYQR201810080).

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MZ, BC, XZ, and WF conceived and designed the experiments in the manuscript. BC, QZ, and YC performed the experiments. BC, YC, and YW analyzed data, plotted the graphs for figures. BC, MZ, and BZ drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiaoke Zheng.

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Cao, B., Zeng, M., Zhang, Q. et al. Amentoflavone Ameliorates Memory Deficits and Abnormal Autophagy in Aβ25−35-Induced Mice by mTOR Signaling. Neurochem Res (2021). https://doi.org/10.1007/s11064-020-03223-8

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Keywords

  • Amentoflavone
  • Autophagy
  • Alzheimer's disease
  • mTOR
  • Aβ 25−35