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Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
Received for publication December 22, 2006.
Accepted for publication May 22, 2007.
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Abstract |
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; Spiegel and Milstien, 2003). Ceramide mediates a wide array of stress signals leading to growth arrest or cell death, whereas S1P exerts prosurvival capabilities by antagonizing ceramide effects. The opposing directions of ceramide- and S1P-mediated signaling gave birth to the concept of a ceramide/S1P biostat and the assumption that the balance between these two sphingolipids could determine whether a cell survives or dies (Cuvillier et al., 1996). The intracellular balance between ceramide and S1P is strongly regulated by sphingosine kinase-1 (SphK1), the enzyme that phosphorylates sphingosine (the catabolite of ceramide) to form S1P. When overexpressed, SphK1 promotes cell survival in response to stresses that increase ceramide content (Olivera et al., 1999; Edsall et al., 2001; Nava et al., 2002; Pchejetski et al., 2005; Bonhoure et al., 2006; Pchejetski et al., 2007) by shifting the ceramide/S1P biostat toward S1P. On the contrary, SphK1 down-regulation is associated with an accumulation of ceramide and has been correlated with cell death induced by anticancer treatments (Nava et al., 2000; Taha et al., 2004; Pchejetski et al., 2005; Bonhoure et al., 2006).
The amyloid-β peptide (Aβ), the main constituent of amyloid plaques, is believed to play a causative role in the neurodegenerative process occurring in Alzheimer's disease (Roher et al., 1993; Selkoe, 2001). Although Aβ-mediated neuronal cell death demonstrates biochemical characteristics of apoptosis, the molecular mechanism underlying Aβ toxicity remains largely undefined. It is noteworthy that increased levels of ceramide have been found in the brain of patients with Alzheimer's disease (Han et al., 2002; Cutler et al., 2004; Satoi et al., 2005), thereby implying that ceramide accumulation could contribute to Alzheimer's disease pathogenesis. In addition, Aβ toxicity was recently shown to be linked with ceramide generation in both cell culture models (Ayasolla et al., 2004; Cutler et al., 2004; Jana and Pahan, 2004; Lee et al., 2004; Yang et al., 2004; Zeng et al., 2005) and an animal model (Alessenko et al., 2004).
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; Carro and Torres-Aleman, 2004). Furthermore, IGF-I prevents Aβ-induced neuronal cell death (Doré et al., 1997; Niikura et al., 2001) including in SH-SY5Y cells (Wei et al., 2002). The TGF-β1 peptide growth factor also protects neurons from a variety of insults (Flanders et al., 1998) including Aβ (Chao et al., 1994; Prehn et al., 1996; Ren and Flanders, 1996; Ren et al., 1997). Levels of TGF-β1 are decreased in human Alzheimer's disease serum (De Servi et al., 2002) and TGF-β receptor expression reduced (Tesseur et al., 2006). Via genetic manipulation of TGF-β1 signaling, it has been demonstrated that reduction of TGF-β1 signaling in neurons of transgenic mice caused age-dependent neurodegeneration and promoted Alzheimer's disease-like pathologic conditions in a mouse model for Alzheimer's disease (Tesseur et al., 2006). Herein, we report that Aβ treatment of SH-SY5Y cells triggered a strong inhibition of SphK1 activity coupled with an elevation of the ceramide/S1P biostat, in a redox-sensitive fashion. Knocking-down SphK1 by an RNA interference strategy mimicked the effects of Aβ, whereas its overexpression rendered cells resistant to Aβ. We further established that SphK1 could transduce the prosurvival action of both IGF-I and TGF-β1. Overall, this study strongly suggests that SphK1 could play a critical role in the regulation of Aβ-induced neuronal cell death and the neuroprotective effect of IGF-I and TGF-β1.
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Materials and Methods |
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; Datki et al., 2003), which was controlled by immunohistochemistry with MAP2 (Sigma-Aldrich) and anti-tau Alz50 (gift from Dr. Peter Davies) antibodies. FLAG epitope-tagged wild-type human SphK1 (hSphK1) cDNA and hSphK1 containing the G82D mutation, subcloned into pcDNA3* vector (Pitson et al., 2000), were used for stable transfection in SH-SY5Y cells. Mass pools of stable transfectants were selected in growth medium containing 0.4 mg/ml G418. Empty vector-, wild-type hSphK1-, and hSphK1G82D-transfected SH-SY5Y cells were designated SH-SY5Y/Neo, SH-SY5Y/SphK1, and SH-SY5Y/SphK1-DN, respectively. All experiments were conducted in the presence of 2% FBS.
Materials. Medium, serum, and antibiotics were obtained from Invitrogen (Carlsbad, CA). Aβ peptides (25-35) and (35-25) were from Bachem (Weil am Rhein, Germany) and freshly solubilized in water before treatment. Thioflavine T fluorescent binding and Congo Red spectroscopic assay indicated a high β-sheets content characteristic of amyloid aggregates (data not shown). Escherichia coli diacylglycerol kinase, human IGF-I, human TGF-β1, CA074-Me, and sphingosine kinase inhibitor (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole; CAS number 312636-16-1) inhibitor were from Calbiochem (San Diego, CA). [
-32P]ATP (3000 mCi/mmol) was purchased from PerkinElmer Life and Analytical Sciences (Waltham, MA), and silica gel 60 high-performance TLC (Partisil LK6D) plates were from What-man (Maidstone, UK). N-Acetylcysteine (NAC), hydrogen peroxide (H2O2), and retinoic acid were from Sigma-Aldrich (St. Louis, MO).
Cell Viability and Staining of Apoptotic Nuclei. Cell viability was measured using the MTT dye reduction assay as described previously (Cuvillier and Levade, 2001). Apoptosis was visually assessed by double-staining cells with Syto 13 (1 µM) and propidium iodide (6 µg/ml) for 5 min at 37°C (Pchejetski et al., 2005). The cells were then examined with a Leica fluorescent microscope and apoptotic cells distinguished by condensed, fragmented nuclear regions.
Western Blot Analysis. Western blotting was carried out as reported previously (Cuvillier et al., 1999) Mouse anti-FLAG (Sigma) and mouse anti-β-actin (Sigma) were used as primary antibodies. Proteins were visualized by ECL detection system (Pierce, Madison, WI) using anti-mouse horseradish peroxidase-conjugated IgG (Bio-Rad Laboratories, Hercules, CA).
SphKs Assay and Mass Measurements of Sphingolipids. SphK1 activity was determined in the presence of sphingosine prepared with Triton X-100 (final concentration 0.25%) whereas for assaying SphK2 activity, sphingosine was prepared in bovine serum albumin (final concentration, 4 mg/ml) and 1 M KCl, a condition in which SphK2 is optimal and SphK2 is inhibited (Maceyka et al., 2005). Ceramide and S1P levels were measured and normalized to protein content (Edsall et al., 2000).
RNA Interference. Transient interference was achieved by double-stranded SphK1-specific siRNA 5'-GGGCAAGGCCUUGCAGCUCd(TT)-3' and 5'-GAGCUGCAAGGCCUUGCCCd(TT)-3' or scrambled siRNA (Qiagen, Valencia, CA) using OligofectAMINE reagent (Invitrogen) as reported previously (Pchejetski et al., 2005). In brief, 75 pM siRNA was complexed with a 1:125 final dilution of OligofectAMINE (Invitrogen) reagent and applied to 1 x 105 cells in a final volume of 250 µl of Opti-MEM (Invitrogen) without FBS or antibiotics. After incubation for 4 h at 37°C under 5% CO2, 150 µl of DMEM with 30% FBS was added. Twenty hours later the medium was changed to 1 ml of DMEM with 10% FBS. Cell viability assays and SphK1 activity determinations were performed daily.
Statistical Analysis. The statistical significance of differences between the means of two groups was evaluated by unpaired Student's t test. All statistical tests were two-sided, and the level of significance was set at P < 0.1. Calculations were performed using Instat (GraphPad Software, San Diego, CA).
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; Luetjens et al., 2001; Olivieri et al., 2001; Wei et al., 2002; Pettifer et al., 2004; Arias et al., 2005), Aβ 25-35 peptide induced a strong loss of cell viability in SH-SY5Y cells with an approximate EC50 of 10 µM at 24 h (Fig. 1B). In contrast, the 10 µM reverse Aβ 35-25 peptide treatment was not toxic to SH-SY5Y cells (Fig. 1B), thus confirming the specificity to the observed toxic effects of Aβ 25-35 peptide. Syto 13/propidium iodide staining revealed that the loss of cell viability observed in Aβ 25-35-treated cells could be attributed to apoptosis (Fig. 1B, inset), as confirmed by flow cytometry analysis with Annexin V-propidium iodide (data not shown). Previous studies have recently suggested that Aβ-induced cell death could be mediated by the proapoptotic sphingolipid metabolite ceramide (Jana and Pahan, 2004; Lee et al., 2004; Yang et al., 2004), we thus sought to determine whether not only ceramide but also other bioactive sphingolipids could be implicated in Aβ-induced toxicity. As already reported (Jana and Pahan, 2004; Lee et al., 2004; Yang et al., 2004), Aβ 25-35 treatment resulted in ceramide increase that was detectable as early as 45 min of incubation with a peak at around 3 h (Fig. 1D). It is noteworthy that SphK1 activity was strongly inhibited as soon as 45 min, with a decrease of more than 30% within3hof treatment (Fig. 1C). The SphK1 inhibition was paralleled by a marked decrease in S1P content (Fig. 1E). It is noteworthy that there were no changes in the levels of ceramide and S1P in SH-SY5Y cells incubated with reverse Aβ 35-25 (data not shown), suggesting that down-regulation of the ceramide/S1P biostat was seen only in cells undergoing apoptosis. Treatment with Aβ 25-35 did not significantly alter activity of the other sphingosine kinase isoform (SphK2; 6.3 ± 1.9 pmol/mg/min), the optimal basal activity of which (6.8 ± 1.2 pmol/mg/min) was approximately 5-fold lower than that of optimal SphK1 (31.1 ± 2.3 pmol/mg/min).
Ceramide generation during Aβ-induced cell death has been shown to involve changes in the cellular redox state and/or glutathione metabolism that controls neutral sphingomyelinase activation (Jana and Pahan, 2004; Lee et al., 2004; Yang et al., 2004). Therefore, we sought to determine whether the glutathione precursor NAC could also affect SphK1 activity. NAC totally hampered Aβ 25-35-induced SphK1 down-regulation (Fig. 2A) and prevented cytoxicity (Olivieri et al., 2001), thus implying a redox-sensitive mechanism for Aβ 25-35-mediated inhibition of SphK1. After having established that Aβ 25-35-induced SphK1 inhibition was inhibited by antioxidant NAC, it was of interest to determine whether addition of exogenous H2O2 could mimic the effect of Aβ 25-35 on SphK1 activity. As shown in Fig. 2B, addition of H2O2 led to a strong inhibition of SphK1. It is noteworthy that pretreatment with NAC could fully prevent SphK1 inhibition as well as cytotoxicity (Fig. 2B).
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950 pmol/mg of protein/min (i.e., 30-fold higher compared with that of empty vector-transfected cells). This increase of SphK1 activity led to a shift in the sphingolipid balance and, notably, in the ceramide-to-S1P ratio. The enforced expression of SphK1 in SH-SY5Y diminished the level of total intracellular ceramide in resting cells by 25%. The basal S1P level was increased by 50% (Fig. 3B, inset and right). The role of SphK1 inhibition in cell death induced by Aβ 25-35 peptide was confirmed by cell viability assays, which showed that SphK1-overexpressing SH-SY5Y were 40% more resistant to Aβ 25-35 peptide than SH-SY5Y transfected with empty vector (Fig. 3C). The cytoprotective effect of SphK1 overexpression was illustrated by a significant decrease of the ceramide-to-S1P ratio (Fig. 3D). In addition, SphK1 overexpression could block the loss of cell viability of SH-SY5Y cells treated with H2O2 (cell viability = 59.5 ± 3.9% in SH-SY5Y/Neo versus 85.5 ± 3.6% in SH-SY5Y SphK1, P < 0.001).
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The Manipulation of the Ceramide/Sphingosine 1-Phosphate Rheostat by Sphingosine Kinase-1 Silencing Promotes Cell Death. To establish proof of concept that SphK1 down-regulation has a critical effectiveness on the cytotoxicity of Aβ 25-35, we examined the effects of siRNA targeted against SphK1 (Pchejetski et al., 2005; Bonhoure et al., 2006; Pchejetski et al., 2007) on SphK1 activity and SH-SY5Y viability. SphK1 activity was strongly decreased compared with scrambled siRNA (Fig. 4A). This was further illustrated by reduction in S1P content (Fig. 4A, inset). Western blot analysis revealed a significant down-regulation of the SphK1 protein in SH-SY5Y/SphK1 cells after siRNA treatment for 72 h (Fig. 4B). The decrease in SphK1 activity was accompanied by an increase in the ceramide to S1P ratio (Fig. 4C) and a substantial loss of cell viability (Fig. 4D). These results clearly indicate that SphK1 is required for cell survival and that the lowering of SphK1 may be crucial to the execution of cell death as recently reported in breast (Taha et al., 2006) and prostate adenocarcinoma (Pchejetski et al., 2005), leukemia cells (Taha et al., 2004; Bonhoure et al., 2006), as well as in cardiomyocytes (Pchejetski et al., 2007).
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; Wei et al., 2002). In agreement with previous reports (Wei et al., 2002), incubation of SH-SY5Y cells with 75 ng/ml IGF-I had a pronounced cytoprotective impact toward Aβ 25-35 peptide (Fig. 5A). Because SphK1 overexpression enhanced survival of SH-SY5Y in response to Aβ 25-35 peptide (Fig. 3C), it was of interest to determine whether SphK1 could be involved in a survival pathway such as the IGF-I one. Figure 5B shows that IGF-I markedly and rapidly up-regulated SphK1 activity (maximum within 60 min of incubation). This increase of SphK1 activity translated into a shift in the sphingolipid balance toward S1P: the level of ceramide was decreased, whereas S1P level was strongly increased (Fig. 5B, inset). To further evaluate the contribution of SphK1 in the cytoprotective effect of IGF-I, we generated SH-SY5Y cells overexpressing SphK1G82D, a catalytically inactive form of SphK1. In contrast to SH-SY5Y/SphK1 cells (Fig. 3B), overexpression of SphK1G82D produced no detectable increase in basal SphK1 activity compared with empty vector-transfected cells (data not shown). Although this mutation did not have any effect on basal SphK1 activity, it did noticeably prevent its stimulation by IGF-I (Fig. 6A), indicating that the mutated SphK1 could function as a dominant-negative (Pitson et al., 2000; Bonhoure et al., 2006). We next evaluated the prosurvival impact IGF-I in SH-SY5Y/SphK1G82D cells when challenged with Aβ 25-35 peptide. Only a partial resistance to Aβ was found (Fig. 6B, left), hence suggesting that SphK1 was to a large extent accounting for the cytoprotective effect of IGF-I (Fig. 6, B, left, versus C). Furthermore, the role of SphK1 was also examined by performing experiments with 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole, known as the most selective SphK1 pharmacological inhibitor available (French et al., 2003). Figure 6C shows that this SphK1 inhibitor could significantly block the cytoprotective effect of IGF-I in a dose-dependent fashion, in a similar manner to the SphK1-DN cell line model (Fig. 6B). We also investigated whether siRNA targeted against SphK1 could have an impact on the cytoprotective effect of IGF-I against Aβ. The prosurvival effect of IGF-I was significantly reduced in SphK1 siRNA-treated SH-SY5Y cells with respect to scrambled siRNA-treated cells (Fig. 6C). As a whole, our results suggest that IGF-I protected against Aβ-induced cell death by markedly up-regulating SphK1.
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The TGF-β1 Protective Effect Against Aβ Peptide Cytotoxicity Involves Sphingosine Kinase-1 Activation. A number of studies have established that peptide growth factor, TGF-β1 can protect against the damaging effects of Aβ in human fetal brain cell cultures (Chao et al., 1994), in primary hippocampal neurons (Prehn et al., 1996; Ren and Flanders, 1996), in differentiated human teratocarcinoma cells (Ren et al., 1997), and in neuroblastoma cell line models (Ren and Flanders, 1996). Pretreatment of SH-SY5Y/Neo cells with 10 ng/ml TGF-β1 led to a pronounced cytoprotective effects toward Aβ 25-35 peptide (Fig. 7A) in agreement with previous studies (Ren and Flanders, 1996). Similar to IGF-I, we found a weaker protection from Aβ 25-35 peptide in SH-SY5Y/SphK1G82D cells coincubated with TGF-β1 (Fig. 7A), and a slightly higher protection in SH-SY5Y cells overexpressing SphK1 (Fig. 7A), implying that SphK1 was a key regulator for the cytoprotective effect of TGF-β1. It has been reported that TGF-β1 could increase SphK1 activity in dermal fibroblasts (Yamanaka et al., 2004). We therefore asked whether SphK1 activity could be stimulated in our cell system in response to TGF-β1. As shown in Fig. 6B, SphK1 was found to be rapidly activated after exposure of SH-SY5Y/Neo to TGF-β1. It is noteworthy that the dominant-negative SH-SY5Y/SphK1G82D cells, in contrast to SH-SY5Y/Neo, did not display SphK1 activation upon TGF-β1 treatment (Fig. 7B, right). The increase of SphK1 activity in SH-SY5Y/Neo cells led to a shift in the sphingolipid balance toward S1P: the level of ceramide was slightly decreased, whereas the S1P level was increased by almost 50% (Fig. 7B). As anticipated, there were no significant changes in the levels of ceramide and S1P in the dominant-negative SH-SY5Y/SphK1G82D cells after treatment with TGF-β1 (Fig. 7C).
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Discussion |
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).
Although the mechanism by which Aβ-peptides induce neuronal loss is poorly understood, a wealth of reports support the notion that ceramide could be a mediator of Aβ-induced toxicity. Ceramide generation by a n-SMase-mediated sphingomyelin degradation in response to Aβ treatment was indeed described both in vitro and in vivo (Alessenko et al., 2004; Ayasolla et al., 2004; Cutler et al., 2004; Jana and Pahan, 2004; Lee et al., 2004; Yang et al., 2004; Zeng et al., 2005). The generation of ceramide during Aβ-induced neuronal cell death is instrumental as for its blockade by n-SMase antisense oligonucleotides, pharmacological n-SMase inhibitors or antioxidants such as the glutathione (GSH) precursor NAC, diphenyl iodonium can hinder the cytotoxic effect of Aβ-peptides (Jana and Pahan, 2004; Lee et al., 2004; Yang et al., 2004). It has been hypothesized that the decrease in GSH level observed after Aβ exposure (Müller et al., 1997; Pereira et al., 1999) could activate n-SMase, therefore leading to ceramide production (Lee et al., 2004). In this study, we establish that not only is the proapoptotic ceramide produced during Aβ-induced neuronal cell death, but also the levels of the prosurvival S1P are diminished as a result of SphK1 down-regulation, thus tilting the ceramide/S1P biostat toward ceramide, as previously observed in tumor cells after anticancer treatments (Nava et al., 2000; Taha et al., 2004; Pchejetski et al., 2005; Bonhoure et al., 2006). There was up to a 3-fold increase in the ceramide/S1P ratio at 3-h incubation time (calculated from the relative amounts of ceramide and S1P levels shown in Fig. 1, D and E, respectively; 1.75:0.65).
Oxidative stress—which is suggested to play a central role in Aβ-induced toxicity and Alzheimer's disease—seemed to be instrumental for mediating SphK1 down-regulation by Aβ peptide because the GSH precursor NAC could impede SphK1 inhibition. Moreover, direct addition of H2O2 also triggered SphK1 inhibition that could be blocked by NAC, and H2O2-induced cell death was overcome by SphK1 overexpression. Such a role for oxidative stress in controlling SphK1 activity has been recently reported in cardiomyocytes after ischemia/reperfusion (Pchejetski et al., 2007). With respect to the significance of SphK1 inhibition during Aβ-induced cell death, one can anticipate it as a means to make sure that the ceramide produced—in response to Aβ—will not give rise to augmented prosurvival S1P. It should be noted that SphK1 inhibition could be seen after treatment of leukemic cells with C2-ceramide (Bonhoure et al., 2006), a cell-permeable analog of natural ceramide, which is known to be metabolized to produce natural long-chain ceramides when added to the cells (Abe et al., 1996). It is noteworthy that C2-ceramide-induced cell death in SH-SY5Y cells can be blocked by SphK1 overexpression (data not shown).
As a proof of the strategic role for SphK1 in regulating Aβ-induced neuronal cell death, our study showed that SphK1 enforced expression markedly inhibited the cytotoxicity of the Aβ peptide. These results are in line with previous reports establishing that SphK1 overexpression can offer protection against proapoptotic stimuli, including serum withdrawal, short-chain ceramides, or anticancer drugs (Olivera et al., 1999; Edsall et al., 2001; Nava et al., 2002; Pchejetski et al., 2005; Bonhoure et al., 2006). Enhanced SphK1 activity is known to reduce ceramide levels by driving ceramide metabolism toward the generation of S1P, which blocks the apoptotic machinery (Pchejetski et al., 2005, 2007; Bonhoure et al., 2006). We further confirmed the specific role of SphK1 by showing that siRNA against SphK1 induced a strong loss of cell viability, thus implying that SphK1 was required for survival of SH-SY5Y cells and that its inhibition was a key feature in apoptosis. Loss of SphK1 has been recently shown to activate the intrinsic pathway of apoptosis through enhanced oligomerization of Bax in the mitochondrial membrane, resulting in cytochrome c release and downstream caspase activation (Taha et al., 2006).
Last, our studies not only demonstrated that SphK1 inhibition was required for Aβ-toxicity in SH-SY5Y cells but also established for the first time that SphK1 was a major transducer of two important growth factors, IGF-I and TGF-β1, whose neuroprotective effects against Aβ are well recognized (Flanders et al., 1998; Carro and Torres-Aleman, 2004; Tesseur et al., 2006). Both IGF-I and TGF-β1 triggered a rapid stimulation of SphK1 activity, tipping the ceramide/S1P balance toward S1P, which in turn could protect SH-SY5Y cells from Aβ-toxicity. The activation of SphK1 was essential for the action of IGF-I and TGF-β1 because a dominant-negative form of SphK1 or its pharmacological inhibition or knocking-down by RNA interference strategy could markedly impede their cytoprotective effect against Aβ peptide.
As a whole, this report shows for the first time the implication of SphK1 in the regulation of death and survival of Aβ-treated neuronal cells, highlighting the notion that the ceramide/S1P biostat could be a regulator of life and death of neurons. The capability of SphK1 to promote neuronal survival suggests that analogs of S1P or stimulators of SphK1 activity might provide a strategy toward forestalling the symptoms of Alzheimer's disease.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: S1P, sphingosine 1-phosphate; SphK1, sphingosine kinase-1; Aβ, amyloid-β; IGF-I, insulin-like growth factor I; TGF-β, transforming growth factor; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; TLC, thin-layer chromatography; NAC, N-acetylcysteine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; siRNA, small interfering RNA; n-SMase, neutral sphingomyelinase; CA074-Me, [L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl]-L-isoleucyl-L-proline methyl ester.
Address correspondence to: Dr Olivier Cuvillier, Institut de Pharmacologie et de Biologie Structurale, CNRS UMR 5089, 31077 Toulouse Cedex 4, France. E-mail: olivier.cuvillier{at}ipbs.fr
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