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Sphingosine Kinase-1 Protects Differentiated N2a Cells Against Beta-Amyloid25–35-Induced Neurotoxicity Via the Mitochondrial Pathway

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Abstract

Although the etiology of Alzheimer’s disease (AD) is not fully understood, multiple lines of evidence suggests the importance of amyloid-β (Aβ) in the initiation/progression of the disease. Aβ has been shown to induce neuronal apoptosis via the sphingomyelin/ceramide pathway. This study was designed to elucidate whether the sphingosine kinase-1 (SPK1), a critical regulator of the ceramide/sphingosine 1-phosphate rheostat, plays a pivotal role in the regulation of death and survival of differentiated neuro-2a cells in response to beta-amyloid peptide fragment 25–35 (Aβ25–35). These results show that the expression of SPK1 was markedly decreased in Aβ25–35-induced neurotoxicity, as evidenced by the decreased cell viability and the increased apoptotic rate. Overexpression of SPK1 significantly attenuated Aβ25–35-induced neurotoxicity, whereas silencing the expression of SPK1 exacerbated it. Moreover, overexpression of SPK1 can significantly attenuate Aβ25–35-induced upregulation of Bax and rehabilitate the level of Bcl-2; concomitantly, it can ameliorate mitochondrial ultrastructure. These studies demonstrate that overexpression of SPK1 may moderate Aβ25–35-induced neurotoxicity by regulating the Bcl-2/Bax ratio and improving mitochondrial ultrastructure. Based on these findings, SPK1 is a potential therapeutic target for AD.

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Acknowledgments

This project was supported by the Chinese National Science Foundation (81070879). We thank Dr. Haifeng Duan (Department of Experimental Hematology, Beijing Institute of Radiation Medicine) for the plasmids encoding wild-type hSPK1.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Dadao, Wuhan, 430022, Hubei Province, China

    Yang Yang, Min Wang, Jing Hu, Shenggang Sun & Gang Li

  2. Department of Geriatrics, Affiliated Hospital of Binzhou Medical University, Binzhou, 256603, China

    Yang Yang

  3. Department of Respiratory, Affiliated Hospital of Binzhou Medical University, Binzhou, 256603, China

    Bingjie Lv

  4. Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Rong Ma & Yaoyan Dun

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  1. Yang Yang
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  2. Min Wang
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Correspondence to Gang Li.

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Yang, Y., Wang, M., Lv, B. et al. Sphingosine Kinase-1 Protects Differentiated N2a Cells Against Beta-Amyloid25–35-Induced Neurotoxicity Via the Mitochondrial Pathway. Neurochem Res 39, 932–940 (2014). https://doi.org/10.1007/s11064-014-1290-6

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  • DOI: https://doi.org/10.1007/s11064-014-1290-6

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