Hydrogen Sulfide Inhibits A2A Adenosine Receptor Agonist Induced β-Amyloid Production in SH-SY5Y Neuroblastoma Cells via a cAMP Dependent Pathway

Alzheimer's disease (AD) is the leading cause of senile dementia in today's society. Its debilitating symptoms are manifested by disturbances in many important brain functions, which are influenced by adenosine. Hence, adenosinergic system is considered as a potential therapeutic target in AD treatment. In the present study, we found that sodium hydrosulfide (NaHS, an H2S donor, 100 mu M) attenuated HENECA (a selective A2A receptor agonist, 10-200 nM) induced beta-amyloid (1-42) (A beta 42) production in SH-SY5Y cells. NaHS also interfered with HENECA-stimulated production and post-translational modification of amyloid precursor protein (APP) by inhibiting its maturation. Measurement of the C-terminal APP fragments generated from its enzymatic cleavage by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) showed that NaHS did not have any significant effect on beta-secretase activity. However, the direct measurements of HENECA-elevated gamma-secretase activity and mRNA expressions of presenilins suggested that the suppression of A beta 42 production in NaHS pretreated cells was mediated by inhibiting gamma-secretase. NaHS induced reductions were accompanied by similar decreases in intracellular cAMP levels and phosphorylation of cAMP responsive element binding protein (CREB). NaHS significantly reduced the elevated cAMP and A beta 42 production caused by forskolin (an adenylyl cyclase, AC agonist) alone or forskolin in combination with IBMX (a phosphodiesterase inhibitor), but had no effect on those caused by IBMX alone. Moreover, pretreatment with NaHS significantly attenuated HENECA-elevated AC activity and mRNA expressions of various AC isoforms. These data suggest that NaHS may preferentially suppress AC activity when it was stimulated. In conclusion, H2S attenuated HENECA induced A beta 42 production in SH-SY5Y neuroblastoma cells through inhibiting gamma-secretase via a cAMP dependent pathway.