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Hydrogen sulfide inhibits A2A adenosine receptor agonist induced β-amyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway.

Nagpure BV, Bian JS - PLoS ONE (2014)

Bottom Line: 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.In conclusion, H2S attenuated HENECA induced Aβ42 production in SH-SY5Y neuroblastoma cells through inhibiting γ-secretase via a cAMP dependent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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.

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Related in: MedlinePlus

Schematic diagram showing the inhibitory effect of H2S on HENECA induced Aβ generation in SH-SY5Y cells.APP is an integral membrane protein which undergoes post-translational modification such as glycosylation during its transfer through intracellular secretory pathway. The mature isoform of APP (i.e. APP holoprotein) is then acted upon by β- and γ-secretases to generate Aβ. The A2A receptor agonist, HENECA, induces production of Aβ42 in SH-SY5Y cells via cAMP/PKA/CREB pathway. It enhances both synthesis and maturation processes of APP increasing total APP production. It also stimulates γ-secretase activity in mAPP cleavage resulting in Aβ generation. H2S not only interferes with the step of APP maturation, but also attenuates the production of APP holoprotein. By inhibiting AC (and subsequent cAMP production), H2S also inhibits γ-secretase activity. It ultimately leads to decreased production in Aβ.
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pone-0088508-g009: Schematic diagram showing the inhibitory effect of H2S on HENECA induced Aβ generation in SH-SY5Y cells.APP is an integral membrane protein which undergoes post-translational modification such as glycosylation during its transfer through intracellular secretory pathway. The mature isoform of APP (i.e. APP holoprotein) is then acted upon by β- and γ-secretases to generate Aβ. The A2A receptor agonist, HENECA, induces production of Aβ42 in SH-SY5Y cells via cAMP/PKA/CREB pathway. It enhances both synthesis and maturation processes of APP increasing total APP production. It also stimulates γ-secretase activity in mAPP cleavage resulting in Aβ generation. H2S not only interferes with the step of APP maturation, but also attenuates the production of APP holoprotein. By inhibiting AC (and subsequent cAMP production), H2S also inhibits γ-secretase activity. It ultimately leads to decreased production in Aβ.

Mentions: In a nutshell, current study suggests beneficial therapeutic role of H2S in AD as it interferes with HENECA stimulated Aβ42 production by attenuating APP maturation and inhibiting γ-secretase via a cAMP dependent pathway (Fig 9). By unraveling the underlying mechanisms of action, the inhibitory actions of H2S on adenosine A2A receptor signal transduction can be deeply studied and thus can be tweaked to gain the maximum therapeutic efficiency.


Hydrogen sulfide inhibits A2A adenosine receptor agonist induced β-amyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway.

Nagpure BV, Bian JS - PLoS ONE (2014)

Schematic diagram showing the inhibitory effect of H2S on HENECA induced Aβ generation in SH-SY5Y cells.APP is an integral membrane protein which undergoes post-translational modification such as glycosylation during its transfer through intracellular secretory pathway. The mature isoform of APP (i.e. APP holoprotein) is then acted upon by β- and γ-secretases to generate Aβ. The A2A receptor agonist, HENECA, induces production of Aβ42 in SH-SY5Y cells via cAMP/PKA/CREB pathway. It enhances both synthesis and maturation processes of APP increasing total APP production. It also stimulates γ-secretase activity in mAPP cleavage resulting in Aβ generation. H2S not only interferes with the step of APP maturation, but also attenuates the production of APP holoprotein. By inhibiting AC (and subsequent cAMP production), H2S also inhibits γ-secretase activity. It ultimately leads to decreased production in Aβ.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921165&req=5

pone-0088508-g009: Schematic diagram showing the inhibitory effect of H2S on HENECA induced Aβ generation in SH-SY5Y cells.APP is an integral membrane protein which undergoes post-translational modification such as glycosylation during its transfer through intracellular secretory pathway. The mature isoform of APP (i.e. APP holoprotein) is then acted upon by β- and γ-secretases to generate Aβ. The A2A receptor agonist, HENECA, induces production of Aβ42 in SH-SY5Y cells via cAMP/PKA/CREB pathway. It enhances both synthesis and maturation processes of APP increasing total APP production. It also stimulates γ-secretase activity in mAPP cleavage resulting in Aβ generation. H2S not only interferes with the step of APP maturation, but also attenuates the production of APP holoprotein. By inhibiting AC (and subsequent cAMP production), H2S also inhibits γ-secretase activity. It ultimately leads to decreased production in Aβ.
Mentions: In a nutshell, current study suggests beneficial therapeutic role of H2S in AD as it interferes with HENECA stimulated Aβ42 production by attenuating APP maturation and inhibiting γ-secretase via a cAMP dependent pathway (Fig 9). By unraveling the underlying mechanisms of action, the inhibitory actions of H2S on adenosine A2A receptor signal transduction can be deeply studied and thus can be tweaked to gain the maximum therapeutic efficiency.

Bottom Line: 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.In conclusion, H2S attenuated HENECA induced Aβ42 production in SH-SY5Y neuroblastoma cells through inhibiting γ-secretase via a cAMP dependent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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.

Show MeSH
Related in: MedlinePlus