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The Neuroprotective Effects of Justicidin A on Amyloid Beta25–35-Induced Neuronal Cell Death Through Inhibition of Tau Hyperphosphorylation and Induction of Autophagy in SH-SY5Y Cells

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Abstract

Justicidin A is a structurally defined arylnaphthalide lignan, which has been shown anti-cancer activity; however, the neuroprotective effect of justicidin A is still untested. In this study, we investigated the action of justicidin A on amyloid beta (Aβ)25–35-induced neuronal cell death via inhibition of the hyperphosphorylation of tau and induction of autophagy in SH-SY5Y cells. Pretreatment with justicidin A significantly elevated cell viability in cells treated with Aβ25–35. Western blot data demonstrated that justicidin A inhibited the Aβ25–35-induced up-regulation the levels of hyperphosphorylation of tau in SH-SY5Y cells. In addition, treatment with justicidin A significantly induced autophagy as measured by the increasing LC3 II/I ratio, an important autophagy marker. These studies showed that justicidin A inhibited activity of glycogen synthase kinase-3beta (GSK-3β), which is an important kinase in up-stream signaling pathways; inhibited hyperphosphorylation of tau in AD; and enhanced activity of AMP-activated protein kinase (AMPK), which is the key molecule for both hyperphosphorylation of tau and induction of autophagy. These data provide the first evidence that justicidin A protects SH-SY5Y cells from Aβ25–35-induced neuronal cell death through inhibition of hyperphosphorylation of tau and induction of autophagy via regulation the activity of GSK-3β and AMPK, and they also provide some insights into the relationship between tau protein hyperphosphorylation and autophagy. Thus, we conclude that justicidin A may have a potential role for neuroprotection and, therefore, may be used as a therapeutic agent for AD.

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Acknowledgments

This research was supported by the Institutional Program of the Korea Institute of Science and Technology (2Z04690), the Bio-Synergy Research Project (NRF-2012M3A9C4048793) and the Bio and Medical Technology Development Program (NRF-2015M3A9A5030735) of the Ministry of Science, ICT, and Future Planning through the National Research Foundation, Republic of Korea.

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  1. Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, 210-340, Republic of Korea

    Ming-Yao Gu, Joonki Kim & Hyun Ok Yang

  2. Department of Biological Chemistry, University of Science and Technology (UST), Daejeon, 305-350, Republic of Korea

    Ming-Yao Gu & Hyun Ok Yang

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Correspondence to Hyun Ok Yang.

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Gu, MY., Kim, J. & Yang, H.O. The Neuroprotective Effects of Justicidin A on Amyloid Beta25–35-Induced Neuronal Cell Death Through Inhibition of Tau Hyperphosphorylation and Induction of Autophagy in SH-SY5Y Cells. Neurochem Res 41, 1458–1467 (2016). https://doi.org/10.1007/s11064-016-1857-5

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  • DOI: https://doi.org/10.1007/s11064-016-1857-5

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