Abstract Hydrogen sulfide (H 2S) is now identified as a new neuromodulator. Increasing evidence suggest that H 2S may play an important role in the progression of Alzheimer's disease (AD). The aim of the present study is to investigate the effects of H 2S on beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) expression and amyloid beta (Aβ) secretion in PC12 cells. The levels of BACE-1 mRNA were measured by quantitative polymerase chain reaction analysis. BACE-1 protein levels were assessed by Western blot. Cellular culture medium levels of Aβ1-42 were analyzed by ELISA. We found that sodium hydrosulfide (NaHS), a H 2S donor, decreased BACE-1 mRNA and protein levels and Aβ1-42 release. Furthermore, NaHS promoted the phosphorylation of Akt and ERK but not JNK or p38 MAPK. However, the effects of NaHS on BACE-1 expression and Aβ1-42 secretion were abolished by inhibitors of phosphatidylinositol 3-kinase (PI3-K), but not of mitogen-activated protein kinase kinases (MEK). Our data indicate that H 2S reduces BACE-1 expression in PC12 cells via activation of PI3-K/Akt signaling pathways. H 2S releasing drugs may have therapeutic potential in AD patients.