Sphingosine kinases/sphingosine-1-phosphate and death Signalling in APP-transfected cells.
It has been postulated that disturbances in the sphingolipid metabolism play a key role in the pathogenesis of Alzheimer's disease (AD). An alteration in sphingosine kinases 1, 2 (SphK1/2) and sphingosine-1-phosphate (S1P) was recently reported in AD. However, the effect of AD-related amyloid beta (Aβ) peptides on SphK1/2 and the role of S1P in Aβ toxicity have not been fully elucidated. In this study the relationship between the Aβ concentration and SphK1/2 expression/activity was analysed in PC12 cells transfected with the Aβ precursor protein, wild-type (APPwt) or bearing a double Swedish mutation (APPsw). The role of SphK(s)/S1P in cell survival and death was also investigated. Our results indicated that endogenously liberated Aβ significantly decreases expression and activity of SphK1/2. The SphK(s) inhibitor (SKI II, 10 μM) decreased the viability of APPwt, APPsw as well as empty vector-transfected PC12 control cells. Our data demonstrated that expression of S1P receptor-1 (S1P1) was significantly reduced in APP-transfected cells. The effect of S1P applied exogenously was cell type-dependent. In control and APPwt cells S1P reduced the effect of the SphK1 inhibitor on death signalling. Conversely, it decreased the survival of APPsw cells and had no protective effect on cells treated with SKI II. Using the S1P1 agonist (SEW2871, 5 μM) and antagonist (W123, 20 μM), we demonstrated that the cytoprotective effect of S1P was receptor-independent. Summarising, we showed that Aβ peptides evoke down-regulation of gene expression and activity for SphK(s) and S1P1. Inhibition of SphK(s) significantly decreased cell survival. The effect of exogenous S1P depended on the concentration of Aβ peptides.
Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106, Warsaw, Poland.
Magdalena
M
Gassowska
Magdalena
M
Cieslik
Anna
A
Wilkaniec
Joanna B
JB
Strosznajder
D016564:Amyloid beta-Protein Precursor / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016716:PC12 Cells; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014162:Transfection / Q000379:methods*; D000099157:Sphingosine Kinase
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate