Ceramide and Ceramide 1 Phosphate in the Brain

  • Akhlaq A. Farooqui


Ceramide (N-acylsphingosine) forms the backbone of all complex sphingolipids. It is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups (varying in length from C14 to C26) (Fig. 8.1). In addition to serving as a precursor to complex sphingolipids, ceramide is a potent signaling molecule capable of regulating vital cellular functions.


Amyotrophic Lateral Sclerosis Major Depressive Disorder Alzheimer Disease Amyotrophic Lateral Sclerosis Patient Alzheimer Disease Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aberg M.A., Aberg N.D., Hedbacker H., Oscarsson J., Eriksson P.S.(2000). Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J. Neurosci. 20:2896–2903.PubMedGoogle Scholar
  2. Adam-Klages S., Schwandner R., Adam D., Kreder D., Bernardo K., and Kronke M. (1998). Distinct adapter proteins mediate acid versus neutral sphingomyelinase activation through the p55 receptor for tumor necrosis factor. J. Leukoc. Biol. 63:678–682.PubMedGoogle Scholar
  3. Adibhatla R.M., and Hatcher J.F. (2010). Protection by D609 through cell-cycle regulation after stroke. Mo.l Neurobiol. 41:206–217.CrossRefGoogle Scholar
  4. Arana L., Gangoiti P., Ouro A., Trueba M., and Gomez-Munoz A. (2010). Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis. 9:15.PubMedCrossRefGoogle Scholar
  5. Arboleda G., Morales L.C., benitez B., and Arboleda H. (2009). Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration. Brain Res. Rev. 59:333–346.PubMedCrossRefGoogle Scholar
  6. Arboleda G., Cárdenas Y., Rodríguez Y., Morales L.C., Matheus L., and Arboleda H. (2010). Differential regulation of AKT, MAPK and GSK3beta during C(2)-ceramide-induced neuronal death. Neurotoxicology. 2010 Aug 7. [Epub ahead of print].Google Scholar
  7. Arévalo J. C. and Wu S. H. (2006). Neurotrophin signaling: many exciting surprises! Cell. Mol. Life Sci. 63:1523–1537.CrossRefGoogle Scholar
  8. Ballou L.R., Laulederkind S.J., Roslouirc E.F., and Roghow R. (1996). Ceramide signalling and the immune response. Biochim. Biophys. Acta 1301:273–287.PubMedGoogle Scholar
  9. Barrett G. L. (2000). The p75 neurotrophin receptor and neuronal apoptosis. Prog. Neurobiol. 61:205–229.PubMedCrossRefGoogle Scholar
  10. Beaulieu J.M. and Julien J.P. (2003). Peripherin-mediated death of motor neurons rescued by overexpression of neurofilament NF-H proteins. J. Neurochem. 85:248–256.PubMedCrossRefGoogle Scholar
  11. Belgardt B.F., Mauer J., and Brüning J.C. (2010). Novel roles for JNK1 in metabolism. Aging (Albany NY). 2010 Aug 3. [Epub ahead of print].Google Scholar
  12. Bhakar A.L., Howell J.L., Paul C.E., Salehi A.H., Becker E.B., Said F., Bonni A., and Barker P.A. (2003). Apoptosis induced by p75NTR overexpression requires Jun kinase-dependent phosphorylation of Bad. J Neurosci 23:11373–11381.PubMedGoogle Scholar
  13. Boath A., Graf C., Lidome E., Ullrich T., Nussbaumer P., and Bornancin F. (2008) Regulation and traffic of ceramide 1-phosphate produced by ceramide kinase: comparative analysis to glucosylceramide and sphingomyelin. J. Biol. Chem. 283:8517–8526.PubMedCrossRefGoogle Scholar
  14. Bourbon N.A., Yun J., and Kester M. (2000). Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. J. Biol. Chem. 275:35617–35623.PubMedCrossRefGoogle Scholar
  15. Brann A.B., Tcherpakov M., Williams I.M., Futerman A.H., and Fainzilber M. (2002). Nerve growth factor-induced p75-mediated death of cultured hippocampal neurons is age-dependent and transduced through ceramide generated by neutral sphingomyelinase. J Biol Chem 277:9812–9818.PubMedCrossRefGoogle Scholar
  16. Brugg B., Michel P.P., Agid Y., and Ruberg M. (1996). Ceramide induces apoptosis in cultured mesencephalic neurons. J Neurochem. 66:733–739.PubMedCrossRefGoogle Scholar
  17. Buxbaum J.D., Cullen E.I., and Friedhoff L.T. (2002). Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Front Biosci. 7:a50-a59.PubMedCrossRefGoogle Scholar
  18. Carre A., Graf C., Stor S., Mechtcheriakova D., Csonga R., Urtz N., Billich A., Baumruker T., and Bornancin F.(2004). Ceramide kinase targeting and activity determined by its N-terminal pleckstrin homology domain. Biochem. Biophys. Res. Commun. 324:1215–1219.PubMedCrossRefGoogle Scholar
  19. Casaccia-Bonnefil P., Carter B.D., Dobrowsky R.T., and Chao M.V. (1996). Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383:716–719.PubMedCrossRefGoogle Scholar
  20. Chalfant C.E., Kishikawa K., Mumby M.C., Kamibayashi C., Bielawska A., and Hannun Y.A. (1999). Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J. Biol. Chem. 274:20313–20317.PubMedCrossRefGoogle Scholar
  21. Clarke C.J. and Hannun Y.A. (2006). Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochim Biophys Acta. 1758:1893–1901.PubMedCrossRefGoogle Scholar
  22. Condeelis J. and Pollard J.W. (2006). Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell124:263–266.PubMedCrossRefGoogle Scholar
  23. Costantini C., Kolasani R.M.K., and Puglielli, L. (2005). Ceramide and cholesterol: possible connections between normal aging of the brain and Alzheimer’s disease. Just hypotheses or molecular pathways to be identified? Alzheimers. Demen. 1, 43–50.CrossRefGoogle Scholar
  24. Cutler R.G., Kelley J., Storie K., Pedersen W.A., Tammara A., Hatanpaa K., Troncoso J.C., and Mattson M.P. (2004). Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl. Acad. Sci. 101:2070–2075.PubMedCrossRefGoogle Scholar
  25. Cutler R.G. and Mattson M.P. (2001). Sphingomyelin and ceramide as regulators of development and lifespan. Mech. Ageing Dev. 122:895–908.PubMedCrossRefGoogle Scholar
  26. Cutler R.G., Pedersen W.A., Camandola S., Rothstein J.D., and Mattson M.P. (2002). Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis. Ann Neurol. 52:448–457.PubMedCrossRefGoogle Scholar
  27. D’Angelo G., Polishchuk E., Di Tullio G., Santoro M., Di Campli A., Godi A., West G., Bielawski J., Chuang C.C., van der Spoel A.C., Platt F.M., Hannun Y.A., Polishchuk R., Mattjus P., and De Matteis M.A. (2007). Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature. 449:62–67.PubMedCrossRefGoogle Scholar
  28. de la Monte S.M. and Wands J.R.Jr. (2008). Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci. Technol. 2:1101–1113.PubMedGoogle Scholar
  29. de la Monte S.M. (2009). Insulin resistance and Alzheimer’s disease. BMB Rep. 42:475–481.PubMedCrossRefGoogle Scholar
  30. de la Monte S.M., Tong M., Nguyen V., Setshedi M., Longato L., and Wands J.R. (2010). Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. J. Alzheimer Dis. 21:967–984.Google Scholar
  31. Dobrowsky R.T., and Carter B.D. (1998). Coupling of the p75 neurotrophin receptor to sphingolipid signaling. Ann NY Acad Sci 845:32–45.PubMedCrossRefGoogle Scholar
  32. Duan R.D. (2006). Alkaline sphingomyelinase: an old enzyme with novel implications. Biochim. Biophys. Acta 1761:281–291.PubMedGoogle Scholar
  33. Dumitru C.A., Zhang Y., Li X., and Gulbins E. (2007). Ceramide: a novel player in reactive oxygen species-induced signaling? Antioxid Redox Signal 9:1535–1540.PubMedCrossRefGoogle Scholar
  34. El Alwani M., Wu B. X. J., Obeid L. M., and Hannun Y. A. (2006). Bioactive sphingolipids in the modulation of the inflammatory response. Pharmacol. Ther. 112:171–183.CrossRefGoogle Scholar
  35. Euskirchen G., Royce T.E., Bertone P., Martone R., Rinn J.L., Nelson F.K., Sayward F., Luscombe N.M., Miller P., Gerstein M., Weissman S., and Snyder M. (2004). CREB binds to multiple loci on human chromosome 22. Mol. Cell. Biol. 24:3804–3814.PubMedCrossRefGoogle Scholar
  36. Farooqui A.A., Horrocks L.A., and Farooqui T. (2007a). Modulation of inflammation in brain: a matter of fat. J Neurochem. 101:577–599.PubMedCrossRefGoogle Scholar
  37. Farooqui A. A., Horrocks L. A., and Farooqui T. (2007b). Interactions between neural membrane glycerophospholipid and sphingolipid mediators: a recipe for neural cell survival or suicide. J. Neurosci. Res. 85:1834–1850.PubMedCrossRefGoogle Scholar
  38. Farooqui A. A. and Horrocks L. A. (2007). Glycerophospholipids in the Brain: Phospholipases A2 in Neurological Disorders, pp. 1–394. Springer, New York.Google Scholar
  39. Farooqui A.A. (2009). Hot Topics in Neural Membrane Lipidology. Springer, New York.Google Scholar
  40. Farooqui A.A. (2010). Neurochemical Aspects of Neurotraumatic and Neurodegenerative Diseases. Springer, New York.CrossRefGoogle Scholar
  41. Farooqui T. and Farooqui A.A. (2011). Pathogenesis of neurodegenerative diseases: contribution of oxidative stress and neuroinflammation in Molecular Aspects of Oxidative Stress on Cell Signaling in Vertebrates and Invertebrates (Farooqui T and Farooqui A.A. eds), Wiley-Blackwell, Hoboken, New Jersey (In Press).Google Scholar
  42. Feng Y. and Le Blanc M.H. (2006). N-tosyl-L-phenylalanyl-chloromethyl ketone reduces ceramide during hypoxic-ischemic brain injury in newborn rat. Eur. J. Pharmacol. 551:34–40.PubMedCrossRefGoogle Scholar
  43. Gangoiti P., Grando M.H., Wang S.W., Kong J.Y., Steinbrecher U.P., and Gomez-Munoz A. (2008). Ceramide 1-phosphate stimulates macrophage proliferation through activation of the PI3-kinase/PKB, JNK and ERK1/2 pathways. Cell Signal 20:726–736.PubMedCrossRefGoogle Scholar
  44. Goldsmith M., Avni D., Levy-Rimler G., Mashiach R., Emst O., Levi M., Webb B., Meijler M.M., Gray N.S., Rosen H., and Zor T. (2009). A ceramide-1-phosphate analogue, PCERA-1, simultaneously suppresses tumour necrosis factor-alpha and induces interleukin-10 production in activated macrophages. Immunology 127:103–115.PubMedCrossRefGoogle Scholar
  45. Gomez-Muñoz A. (1998). Modulation of cell signalling by ceramides. Biochim. Biophys. Acta Lipids Lipid Metab. 1391:92–109.CrossRefGoogle Scholar
  46. Gómez-Muñoz A. (2006). Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim. Biophys. Acta 1758:2049–2056.PubMedCrossRefGoogle Scholar
  47. Grando M.H., Gangoiti P., Ouro A., Arana L., Gonzalez M., Trueba M., and Gomez-Munoz A. (2009). Ceramide 1-phosphate (C1P) promotes cell migration Involvement of a specific C1P receptor. Cell Signal 21:405–512.CrossRefGoogle Scholar
  48. Guan X. L., He X., Ong W. Y., Yeo W. K., Shui G. H., and Wenk M. R. (2006). Non-targeted profiling of lipids during kainate-induced neuronal injury. FASEB J. 20:1152–1161.PubMedCrossRefGoogle Scholar
  49. Gulbins E., and Li P.L. (2006). Physiological and pathophysiological aspects of ceramide. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290:R11-R26.PubMedCrossRefGoogle Scholar
  50. Han X., Holtzman D., McKeel D.W. jr., Kelley J., and Morris J.C. (2002). Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J. Neurochem. 82:809–818.PubMedCrossRefGoogle Scholar
  51. Haan M.N. (2006). Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer’s disease. Nat. Clin. Pract. Neurol. 2:159–166.PubMedCrossRefGoogle Scholar
  52. Hanada K., Kumagai K., Yasuda S., Miura Y., Kawano M., Fukasawa M., Nishijima M. (2003). Molecular machinery for non-vesicular trafficking of ceramide. Nature 426:803–809.PubMedCrossRefGoogle Scholar
  53. Hannun Y. A. and Obeid L. M. (2002). The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J. Biol. Chem. 277:25847–25850.PubMedCrossRefGoogle Scholar
  54. Hannun Y. A. (1997). Phospholipase A2 is necessary for tumor necrosis factor α-induced ceramide generation in L929 cells. J. Biol. Chem. 272:17196–17203.PubMedCrossRefGoogle Scholar
  55. Haughey N.J., Cutler R.G., Tamara A., McArthur J.C., Vargas D.L., Pardo C.A., Turchan J., Nath A., and Mattson MP. (2004). Perturbation of sphingolipid metabolism and ceramide production in hiv-dementia. Ann Neurol 2004;55:257–267.PubMedCrossRefGoogle Scholar
  56. Haughey N.J., Bandaru V.V., Bae M., and Mattson M.P. (2010). Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochim Biophys Acta. 1801:878–886.PubMedGoogle Scholar
  57. Hayakawa M., Jayadev S., Tsujimoto M., Hannun Y. A., and Ito F. (1996). Role of ceramide in stimulation of the transcription of cytosolic phospholipase A2 and cyclooxygenase 2. Biochem. Biophys. Res. Commun. 220:681–686.PubMedCrossRefGoogle Scholar
  58. He X., Guan X. L., Ong W. Y., Farooqui A. A., and Wenk M. R. (2007). Expression, activity, and role of serine palmitoyltransferase in the rat hippocampus after kainate injury. J. Neurosci. Res. 85:423–432.PubMedCrossRefGoogle Scholar
  59. He X., Huang Y., Li B., Gong C.X., and Schuchman E.H. (2010). Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging. 31:398–408.PubMedCrossRefGoogle Scholar
  60. Heinrich M., Wickel M., Schneider-Brachert W., Sandberg C., Gahr J., Schwandner R., Weber T., Saftig P., Peters C., Brunner J., Kronke M., and Schutze S. (1999). Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J. 18:5252–5263.PubMedCrossRefGoogle Scholar
  61. Herrmann J.L., Bruckheimer E., and McDonnell T.J. (1996). Cell death signal transduction and Bcl-2 function. Biochem. Soc. Trans. 24:1059–1065.PubMedGoogle Scholar
  62. Hicks A. M., DeLong C. J., Thomas M. J., Samuel M., and Cui Z. (2006). Unique molecular signatures of glycerophospholipid species in different rat tissues analyzed by tandem mass spectrometry. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1761:1022–1029.Google Scholar
  63. Hisaki H., Shimasaki H., Ueta N., Kubota M., Nakane M., Nakagomi T., Tamura A., and Mosida H. (2004). In vivo influence of ceramide accumulation induced by treatment with a glucosylceramide synthase inhibitor on ischemic neuronal cell death. Brain Res. 1018:73–77.PubMedCrossRefGoogle Scholar
  64. Huang H. and Tindall D.J. (2007). Dynamic FoxO transcription factors. J Cell Sci. 120:2479–2487.PubMedCrossRefGoogle Scholar
  65. Huwiler A., Brunner J., Hummel R., Vervoordeldonk M., Stabel S., van den Bosch H., and Pfeilschifter J. (1996). Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. Proc. Natl. Acad. Sci. U. S. A. 93:6959–6963.PubMedCrossRefGoogle Scholar
  66. Huwiler A., Johannsen B., Skarstad A., and Pfeilschifter J. (2001). Ceramide binds to the CaLB domain of cytosolic phospholipase A2 and facilitates its membrane docking and arachidonic acid release. FASEB J. 15:7–9.PubMedGoogle Scholar
  67. Hwang Y.H., Tani M., Nakagawa T., Okino N., and Ito M. (2005). Subcellular localization of human neutral ceramidase expressed in HEK293 cells. Biochem. Biophys. Res. Commun. 331:37–42.PubMedCrossRefGoogle Scholar
  68. Jana A., Hogan E.L., and Pahan K. (2009). Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J Neurol Sci. 278:5–15.PubMedCrossRefGoogle Scholar
  69. Jayadev S., Hayter H.L., Andrieu N., Gamard C.J., Liu B., Balu R., Hayakawa M., Ito F., Hannun Y.A. (1997). Phospholipase A2 is necessary for tumor necrosis factor alpha-induced ceramide generation in L929 cells. J Biol Chem. 272:17196–17203.PubMedCrossRefGoogle Scholar
  70. Kalvodova L., Kahya N., Schwille P., Ehehalt R., Verkade P., Drechsel D., and Simons K. (2005). Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem. 280:36815–36823.PubMedCrossRefGoogle Scholar
  71. Kitatani K., Idkowiak-Baldys J., Bielawski J., Taha T.A., Jenkins R.W., Senkal C.E., Ogretmen B., Obeid L.M., and Hannun Y.A. (2006). Protein kinase C-induced activation of a ceramide/protein phosphatase 1 pathway leading to dephosphorylation of p38 MAPK. J. Biol. Chem. 281:36793–36802.PubMedCrossRefGoogle Scholar
  72. Kitatani K., Idkowiak J., and Hannun Y.A. (2008). The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 20:1010–1018.PubMedCrossRefGoogle Scholar
  73. Kornhuber J., Reichel M., Tripal P., Groemer T.W., Henkel A.W., Mühle C., and Gulbins E. (2009). The role of ceramide in major depressive disorder. Eur Arch Psychiatry Clin Neurosci. 259 Suppl 2:S199-204.PubMedCrossRefGoogle Scholar
  74. Kroner Z. (2009). The relationship between Alzheimer’s disease and diabetes: Type 3 diabetes? Altern. Med. Rev. 14:373–379.PubMedGoogle Scholar
  75. Levi M., Meijler M.M., Gomez-Munoz A., and Zor T. (2010). Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1). Mol. Cell Endocrinol. 314:248–255.PubMedCrossRefGoogle Scholar
  76. Lester-Coll N., Rivera E.J., Soscia S.J., Doiron K., Wands J.R., and de la Monte S.M. (2006). Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J. Alzheimer Dis. 9:13–33.Google Scholar
  77. Li X., Becker K.A. and Zhang Y. (2010). Ceramide in redox signaling and cardiovascular diseases. Cell Physiol. Biochem. 26:41–48.PubMedCrossRefGoogle Scholar
  78. Liu G., Kleine L., and Hebert R.L. (1999). Advances in the signal transduction of ceramide and related sphingolipids. Crit. Rev. Clin. Lab. Sci. 36:511–573.PubMedCrossRefGoogle Scholar
  79. Luberto C., Kraveka J. M., and Hannun Y. A. (2002). Ceramide regulation of apoptosis versus differentiation: a walk on a fine line. Lessons from neurobiology. Neurochem. Res. 27:609–617.Google Scholar
  80. Malaplate-Armand C., Florent-Béchard S., Youssef I., Koziel V., Sponne I., Kriem B., Leininger-Muller B., Olivier J. L., Oster T., and Pillot T. (2006). Soluble oligomers of amyloid-β peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol. Dis. 23:178–189.PubMedCrossRefGoogle Scholar
  81. Marchesini N. and Hannun Y. A. (2004). Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem. Cell Biol. 82:27–44.PubMedCrossRefGoogle Scholar
  82. Mao C., and Obeid LM. (2008). Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim Biophys Acta. 1781:424–434.PubMedGoogle Scholar
  83. MacPhee I., and Barker P.A. (1999). Extended ceramide exposure activates the trkA receptor by increasing receptor homodimer formation. J Neurochem. 72:1423–1430.PubMedCrossRefGoogle Scholar
  84. Mathias S., Peña L. A., and Kolesnick R. N. (1998). Signal transduction of stress via ceramide. Biochem. J. 335 ( Pt 3):465–480.PubMedGoogle Scholar
  85. Mitsutake S., Kim T.J., Inagaki Y., Kato M., Yamashita T., and Igarashi Y. (2004). Ceramide kinase is a mediator of calcium-dependent degranulation in mast cells. J. Biol. Chem. 279:17570–17577.PubMedCrossRefGoogle Scholar
  86. Nakamura H., Hirabayashi T., Shimizu M., and Murayama T. (2006). Ceramide-1-phosphate activates cytosolic phospholipase A2α directly and by PKC pathway. Biochem. Pharmacol. 71:850–857.PubMedCrossRefGoogle Scholar
  87. Ogretmen B., and Hannun Y.A. (2004). Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer. 4:604616.PubMedCrossRefGoogle Scholar
  88. Ohanian J. and Ohanian V. (2001). Sphingolipids in mammalian cell signalling. Cell Mol. Life Sci. 58:2053–2068.PubMedCrossRefGoogle Scholar
  89. Pehar M., Vargas M.R., Robinson K.M., Cassina P., Díaz-Amarilla P.J., Hagen T.M., Radi R., Barbeito L., and Beckman J.S. (2007). Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J Neurosci. 27:77777785.PubMedCrossRefGoogle Scholar
  90. Perry R. J. and Ridgway N. D. (2005). Molecular mechanisms and regulation of ceramide transport. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1734:220–234.Google Scholar
  91. Puranam K., Qian W.H., Nikbakht K., Venable M., Obeid L., Hannun Y., and Boustany R.M. (1997). Upregulation of bcl-2 and elevation of ceramide in batten disease. Neuropediatrics 28:37–41.PubMedCrossRefGoogle Scholar
  92. Qin J., Berdyshev E., Goya J., Natarajan V., and Dawson G. (2010). Neurons and oligodendrocytes recycle sphingosine 1-phosphate to ceramide: significance for apoptosis and multiple sclerosis. J. Biol. Chem. 285:14134–14143.PubMedCrossRefGoogle Scholar
  93. Ramsey M.M., Adams M.M., Ariwodola O.J., Sonntag W.E., Weiner J.L. (2005). Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus. J. Neurophysiol. 94:247–254.PubMedCrossRefGoogle Scholar
  94. Riezman H., and van Meer G. (2004). Lipid pickup and delivery. Nat Cell Biol 6: 15–16.PubMedCrossRefGoogle Scholar
  95. Robinson B. S., Hii C. S. T., Poulos A., and Ferrante A. (1997). Activation of neutral sphingomyelinase in human neutrophils by polyunsaturated fatty acids. Immunology 91:274–280.PubMedCrossRefGoogle Scholar
  96. Ruvolo P. P. (2001). Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15:1153–1160.PubMedCrossRefGoogle Scholar
  97. Ruvolo P.P. (2003). Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol. Res. 47:383–392.PubMedCrossRefGoogle Scholar
  98. Sato T., Kageura T., Hashizume T., Hayama M., Kitatani K., and Akiba S. (1999). Stimulation by ceramide of phospholipase A2 activation through a mechanism related to the phospholipase C-initiated signaling pathway in rabbit platelets. J. Biochem. (Tokyo) 125:96–102.Google Scholar
  99. Satoi H., Tomimoto H., Ohtani R., Kitano T., Kondo T., Watanabe M., Oka N., Akiguchi I., Furuya S., Hirabayashi Y., and Okazaki T. (2005). Astroglial expression of ceramide in Alzheimer’s disease brains: a role during neuronal apoptosis. Neuroscience. 130:657–666.PubMedCrossRefGoogle Scholar
  100. Sawai H., Domae N., and Okazaki T. (2005). Current status and perspectives in ceramide-targeting molecular medicine. Curr. Pharmaceut. Design 11:2479–2487.CrossRefGoogle Scholar
  101. Sidkind L.J. (2005). Mitochondrial ceramide and the induction of apoptosis. J. Bioenerg. Biomembr. 37:143–153.CrossRefGoogle Scholar
  102. Smith E. R. and Merrill A. H., Jr. (1995). Differential roles of de novo sphingolipid biosynthesis and turnover in the “burst” of free sphingosine and sphinganine, and their 1-phosphates and N-acyl-derivatives, that occurs upon changing the medium of cells in culture. J. Biol. Chem. 270:18749–18758.PubMedCrossRefGoogle Scholar
  103. Smith W. L. and Merrill A. H., Jr. (2002). Sphingolipid metabolism and signaling minireview series. J. Biol. Chem. 277:25841–25842.PubMedCrossRefGoogle Scholar
  104. Stoica B.A., Morseyan V.A., Knoblach S.M., and Faden A.L., (2005). Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol. Cell Neurosci. 29:355–337.PubMedCrossRefGoogle Scholar
  105. Stratford, S.., Hoehn K..L., Liu F., and Summers, S.A. (2004). Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J. Biol. Chem. 279:36608–36615.PubMedCrossRefGoogle Scholar
  106. Subramanian P., Stahelin R. V., Szulc Z., Bielawska A., Cho W., and Chalfant C. E. (2005). Ceramide 1-phosphate acts as a positive allosteric activator of group IVA cytosolic phospholipase A2 and enhances the interaction of the enzyme with phosphatidylcholine. J. Biol. Chem. 280:17601–17607.PubMedCrossRefGoogle Scholar
  107. Sugiura M., Kono K., Liu H., Shimizugawa T., Minekura H., Spiegel S., and Kohama T. (2002). Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J. Biol. Chem. 277:23294–23300.PubMedCrossRefGoogle Scholar
  108. Sun W., Xu R., Hu W., Jin J., Crellin H.A., Bielawski J., Szulc Z.M., Thiers B.H., Obeid L.M., Mao C. (2007). Upregulation of the Human Alkaline Ceramidase 1 and Acid Ceramidase Mediates Calcium-Induced Differentiation of Epidermal Keratinocytes. J Invest Dermatol 2007;23:23.Google Scholar
  109. Tabatadze N., Savonenko A., Song H., Bandaru V.V., Chu M., and Haughey N.J. (2010). Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice. J Neurosci Res. 88:2940–2951.PubMedGoogle Scholar
  110. Tian H.P., Qiu T.Z., Zhao J., Li L.X., and Guo J. (2009). Sphingomyelinase-induced ceramide production stimulate calcium-independent JNK and PP2A activation following cerebral ischemia. Brain Inj. 23:1073–1080.PubMedCrossRefGoogle Scholar
  111. Tong M. and de la Monte S.M. (2009). Mechanisms of ceramide-mediated neurodegeneration. J. Alzheimer Dis. 16: 705–714.Google Scholar
  112. Vaena de Avalos S., Jones J. A., and Hannun Y. A. (2004). Ceramides. In: Nicolaou A. and Kokotos G. (eds.), Bioactive Lipids. The Oily Press, Bridgwater, England, pp. 135–167.Google Scholar
  113. Vanags D. M., Larsson P., Feltenmark S., Jakobsson P. J., Orrenius S., Claesson H. E., and Aguilar-Santelises M. (1997). Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by TNF plus cycloheximide in U937 cells. Cell Death Differ. 4:479–486.PubMedCrossRefGoogle Scholar
  114. Wheeler D., Knapp E., Bandaru V.V., Wang Y., Knorr D., Poirier C., Mattson M.P., Geiger J.D., and Haughey N.J. (2009). Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. J. Neurochem. 109:1237–1249.PubMedCrossRefGoogle Scholar
  115. White M.F. (2003). Insulin signaling in health and disease. Science. 302:1710–1711.PubMedCrossRefGoogle Scholar
  116. Yu Z.F., Nikolova-Karakashian M., Zhou D., Cheng G., Schuchman E.H., and Mattson M.P. (2000). Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis. J Mol Neurosci. 15:85–97.PubMedCrossRefGoogle Scholar
  117. Zhang Y., Yao B., Delika S., Bayoumy S., Lin X-H., McGinley M., Chan-Hui P.Y., Lichenstein H., and Kolesnick R. (1997). Kinase suppressor of Ras is ceramide-activated protein kinase. Cell. 89:63–72.PubMedCrossRefGoogle Scholar
  118. Zhang Y., Li X., Becker K.A., and Gulbins E. (2009). Ceramide-enriched membrane domains–structure and function. Biochim. Biophys. Acta 1788:178–183.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Molecular and Cellular BiochemistryThe Ohio State UniversityColumbusUSA

Personalised recommendations