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Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice

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Abstract

Hydrogen sulfide (H2S) is now considered to be a gasotransmitter and may be involved in the pathological process of Alzheimer’s disease (AD). A majority of APP is associated with mitochondria and is a substrate for the mitochondrial γ-secretase. The mitochondria-associated APP metabolism where APP intracellular domains (AICD) and Aβ are generated locally and may contribute to mitochondrial dysfunction in AD. Here, we aimed to investigate the ability of H2S to mediate APP processing in mitochondria and assessed the possible mechanisms underlying H2S-mediated AD development. We treated neurons from APP/PS1 transgenic mice with a range of sodium hydrosulfide (NaHS) concentrations. NaHS attenuated APP processing and decreased Aβ production in mitochondria. Meanwhile, NaHS did not changed BACE-1 and ADAM10 (a disintegrin and metalloprotease 10) protein levels, but NaHS (30 μM) significantly increased the levels of presenilin 1(PS1), PEN-2, and NCT, as well as improved the γ-secretase activity, while NaHS (50 μM) exhibits the opposing effects. Furthermore, the intracellular ATP and the COX IV activity of APP/PS1 neurons were increased after 30 μM NaHS treatment, while the ROS level was decreased and the MMP was stabilized. The effect of NaHS differs from DAPT (a non-selective γ-secretase inhibitor), and it selectively inhibited γ-secretase in vitro, without interacting with Notch and modulating its cleavage. The results indicated that NaHS decreases Aβ accumulation in mitochondria by selectively inhibiting γ-secretase. Thus, we provide a mechanistic view of NaHS is a potential anti-AD drug candidate and it may decrease Aβ deposition in mitochondria by selectively inhibiting γ-secretase activity and therefore protecting the mitochondrial function during AD conditions.

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Acknowledgments

We thank Professor Zhang (Associate Professor, Neuroscience Center, the First Affiliated Hospital of Chongqing Medical University) for significant comments and scientific support, and Professor Tang for technical assistance. The study was supported by the National Natural Science Foundation of China (Grant No. 81271222).

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  1. Experimental Research Center, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, No. 1 Youyi Road, Chongqing, 400016, China

    Feng-li Zhao, Pei-feng Qiao, Dan Gao, Meng-jie Liu & Yong Yan

  2. Department of Neurology, The University-Town Hospital of Chongqing Medical University, Chongqing, China

    Ning Yan

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  1. Feng-li Zhao
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Zhao, Fl., Qiao, Pf., Yan, N. et al. Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice. Neurochem Res 41, 1145–1159 (2016). https://doi.org/10.1007/s11064-015-1807-7

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