Hydrogen Sulfide Selectively Inhibits gamma-Secretase Activity and Decreases Mitochondrial A beta Production in Neurons from APP/PS1 Transgenic Mice

摘要

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 gamma-secretase. The mitochondria-associated APP metabolism where APP intracellular domains (AICD) and A beta 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 A beta production in mitochondria. Meanwhile, NaHS did not changed BACE-1 and ADAM10 (a disintegrin and metalloprotease 10) protein levels, but NaHS (30 mu M) significantly increased the levels of presenilin 1(PS1), PEN-2, and NCT, as well as improved the gamma-secretase activity, while NaHS (50 mu M) exhibits the opposing effects. Furthermore, the intracellular ATP and the COX IV activity of APP/PS1 neurons were increased after 30 mu M NaHS treatment, while the ROS level was decreased and the MMP was stabilized. The effect of NaHS differs from DAPT (a non-selective gamma-secretase inhibitor), and it selectively inhibited gamma-secretase in vitro, without interacting with Notch and modulating its cleavage. The results indicated that NaHS decreases A beta accumulation in mitochondria by selectively inhibiting gamma-secretase. Thus, we provide a mechanistic view of NaHS is a potential anti-AD drug candidate and it may decrease A beta deposition in mitochondria by selectively inhibiting gamma-secretase activity and therefore protecting the mitochondrial function during AD conditions.