title: Hydrogen sulfide inhibits A2A adenosine receptor agonist induced β-amyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway.
abstract: 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 µM) attenuated HENECA (a selective A2A receptor agonist, 10-200 nM) induced β-amyloid (1-42) (Aβ42) 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 β-site amyloid precursor protein cleaving enzyme 1 (BACE1) showed that NaHS did not have any significant effect on β-secretase activity. However, the direct measurements of HENECA-elevated γ-secretase activity and mRNA expressions of presenilins suggested that the suppression of Aβ42 production in NaHS pretreated cells was mediated by inhibiting γ-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 Aβ42 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 Aβ42 production in SH-SY5Y neuroblastoma cells through inhibiting γ-secretase via a cAMP dependent pathway.
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Bhushan Vijay
authors: BV
authors: Nagpure
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Jin-Song
authors: JS
authors: Bian
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D000242:Cyclic AMP / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry*; D009447:Neuroblastoma / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D058908:Adenosine A2 Receptor Agonists; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42); D000242:Cyclic AMP; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D006862:Hydrogen Sulfide