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Involvement of α7 nAChR Signaling Cascade in Epigallocatechin Gallate Suppression of β-Amyloid-Induced Apoptotic Cortical Neuronal Insults

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Abstract

Excessive generation and accumulation of the β-amyloid (Aβ) peptide in selectively vulnerable brain regions is a key pathogenic event in the Alzheimer's disease (AD), while epigallocatechin gallate (EGCG) is a very promising chemical to suppress a variety of Aβ-induced neurodegenerative disorders. However, the precise molecular mechanism of EGCG responsible for protection against neurotoxicity still remains elusive. To validate and further investigate the possible mechanism involved, we explored whether EGCG neuroprotection against neurotoxicity of Aβ is mediated through the α7 nicotinic acetylcholine receptor (α7 nAChR) signaling cascade. It was shown in rat primary cortical neurons that short-term treatment with EGCG significantly attenuated the neurotoxicity of Aβ1–42, as demonstrated by increased cell viability, reduced number of apoptotic cells, decreased reactive oxygen species (ROS) generation, and downregulated caspase-3 levels after treatment with 25-μM Aβ1–42. In addition, EGCG markedly strengthened activation of α7nAChR as well as its downstream pathway signaling molecules phosphatidylinositol 3-kinase (PI3K) and Akt, subsequently leading to suppression of Bcl-2 downregulation in Aβ-treated neurons. Conversely, administration of α7nAChR antagonist methyllycaconitine (MLA; 20 μM) to neuronal cultures significantly attenuated the neuroprotection of EGCG against Aβ-induced neurototoxicity, thus presenting new evidence that the α7nAChR activity together with PI3K/Akt transduction signaling may contribute to the molecular mechanism underlying the neuroprotective effects of EGCG against Aβ-induced cell death.

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Acknowledgments

This work was supported by the Natural Science Foundation of China (nos. 81272135 and 30973088) and National High-tech R& D Program of China (2006AA02Z157).

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Authors and Affiliations

  1. Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, China

    Xijing Zhang

  2. Institute of Neurosciences, The Fourth Military Medical University, Xi’an, 710032, China

    Mingmei Wu & Na Luo

  3. Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an, 710032, China

    Fan Lu

  4. Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200217, China

    Zu-Ping He & Hao Yang

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  1. Xijing Zhang
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  2. Mingmei Wu
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  3. Fan Lu
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  4. Na Luo
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  5. Zu-Ping He
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  6. Hao Yang
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Correspondence to Hao Yang.

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Xijing Zhang and Mingmei Wu contributed equally to this work.

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Zhang, X., Wu, M., Lu, F. et al. Involvement of α7 nAChR Signaling Cascade in Epigallocatechin Gallate Suppression of β-Amyloid-Induced Apoptotic Cortical Neuronal Insults. Mol Neurobiol 49, 66–77 (2014). https://doi.org/10.1007/s12035-013-8491-x

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