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.
Highlights
Alzheimer’s disease (AD), which is the most common neurodegenerative disease, is the leading cause of senile dementia [1]
methylthiazolyl tetrazolium (MTT) results showed that both NaHS (Fig 1D) and HENECA (Fig 1E) at the concentration ranges used for the experiments had no effect on cell viability
Accumulating epidemiological, genetic and pharmaceutical studies have shown that there is a convincing role of adenosine signaling in controlling brain damage
Summary
Alzheimer’s disease (AD), which is the most common neurodegenerative disease, is the leading cause of senile dementia [1]. The classical neuro-pathological hallmarks of AD include accumulation of senile plaques in the brain, neuro-fibrillary tangles, synaptic loss and neuronal death [3,4]. Senile plaques consist mainly of a 39–42 amino acid long b-amyloid (Ab) peptide, generated from a larger transmembrane amyloid precursor protein (APP) [5]. Poorly soluble amyloidogenic Ab is derived from sequential cleavage of APP by b- and csecretases [6]. Above-mentioned and other evidences strongly support that APP synthesis and proteolysis are critical events in AD pathogenesis. Drugs targeting these processes are likely to be beneficial for the prevention and treatment of AD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
