The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease

  • A. V. AlessenkoEmail author


The review discusses the functional role of sphingolipids in the pathogenesis of Alzheimer’s disease (AD). Certain evidence exists that the imbalance of sphingolipids such as sphingomyelin, ceramide, sphingosine, sphingosine-1-phosphate and galactosylceramide in the brain of animals and humans, in the cerebrospinal fluid and blood plasma of AD patients plays a crucial role in neuronal function by regulating growth, differentiation and cell death in CNS. Activation of sphingomyelinase (Smase), which leads to the accumulation of the proapoptotic agent, ceramide, can be considered as a new mechanism for AD and may be a prerequisite for the treatment of this disease by using drugs that inhibit SMase activity. The role of sphingolipids as biomarkers for the diagnosis of the early stage of Alzheimer’s disease and monitoring the effectiveness of treatment with new drugs is discussed.


Alzheimer’s disease sphingolipids (sphingomyelin, ceramide, sphingosine, sphingosine-1-phosphate, sulphatides) mass spectrometry of sphingolipids brain cerebrospinal fluid blood plasma biomarkers 

Abbreviations used

amyloid beta peptide


Alzheimer’s Disease


amyloid precursor protein






collision induced dissociation


cerebrospinal fluid


central nervous system










Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gavrilova, S.I., Farmakoterapiya bolezni Al’tzgeimera (Pharmacotherapy of Alzheimer’s Disease), Moscow: Pulse, 2007.Google Scholar
  2. 2.
    Selkoe, D.J., Annu. Rev. Cell. Biol., 1994, vol. 10, pp. 373–403.Google Scholar
  3. 3.
    Mielke, M. and Lyketsos, G., Neuromolecular Med., 2010, vol. 12, pp. 331–340.Google Scholar
  4. 4.
    Haughey, N.J., Bandaru, V.R., Bai, M., and Mattson, M.P., Biochim. Biophys. Acta, 2010, vol. 1801, pp. 878–886.Google Scholar
  5. 5.
    Merrill, A.H., J. Biol. Chem., 2002, vol. 277, pp. 25843–25846.Google Scholar
  6. 6.
    Hannun, Y.A. and Obeid, L.M., Nature Reviews Molecular Cell Biology, 2008, vol. 9, pp. 139–150.Google Scholar
  7. 7.
    Pruett, S.T., Bushnev, A., and Hagedorn, K., J. Lipid Res., 2008, vol. 49, pp. 1621–1639.Google Scholar
  8. 8.
    Pettus, B.J., Chalfant, C.E., and Hannun, Y.A., Biochim. Biophys. Acta, 2002, vol. 1585, pp. 114–125.Google Scholar
  9. 9.
    Buccoliero, R. and Futerman, A.H., Pharmacological Res., 2003, vol. 47, pp. 409–419.Google Scholar
  10. 10.
    Mao, C. and Obeid, L.V., Biochim. Biophys. Acta, 2008, vol. 1781, pp. 424–434.Google Scholar
  11. 11.
    Hakomori, S., Curr. Opin. Hematol., 2003, vol. 10, pp. 16–24.Google Scholar
  12. 12.
    Bielawska, A., Crane, H.M., Liotta, D., Obeid, L.M., and Hannun, Y.A., J. Biol. Chem., 1993, vol. 268, pp. 26226–26232.Google Scholar
  13. 13.
    Alessenko, A.V., in New Research on Alzheimer’s Disease, Welsh, E.M., Ed., 2006, pp. 168–189.Google Scholar
  14. 14.
    Gatt, S., J. Biol. Chem., 1963, vol. 238, pp. 3131–3133.Google Scholar
  15. 15.
    Horres, C.R. and Hannun, Y.A., Neurochem. Res. 2012, Jan. 12 (Epub ahead of print).Google Scholar
  16. 16.
    Spence, M.W., Byers, D.M., Palmer, F.B., and Cook, H.W., J. Biol. Chem., 1989, vol. 264, pp. 5358–5363.Google Scholar
  17. 17.
    Nilsson, A., Biochim. Biophys. Acta, 1969, vol. 176, pp. 339–347.Google Scholar
  18. 18.
    Duan, R.D., Biochim. Biophys. Acta, 2006, vol. 1761, pp. 281–291.Google Scholar
  19. 19.
    Hofmann, K., Tomiuk, S., Wolff, G., and Stoffel, W., Proc. Natl. Acad. Sci. USA, 2000, vol. 97, pp. 5895–5900.Google Scholar
  20. 20.
    Levy, M., Castillo, S., and Goldcorn, T., Biochem. Biophys. Res. Commun., 2006, vol. 344, pp. 900–905.Google Scholar
  21. 21.
    Krut, O., Wiegmann, K., Kashkar, H., Yazdanpahan, B., and Kronke, M., J. Biol. Chem., 2006, vol. 281, pp. 13784–13793.Google Scholar
  22. 22.
    Huitema, K., van den Dikkenberg, J., Brouwers, J.F., and Holthuis, J.C., Embo J., 2004, vol. 23, pp. 33–44.Google Scholar
  23. 23.
    Taffese, F.G., Huitema, K., Hermansson, M., van der Poel, S., van den Dikkenberg, J., Uphoff, A., Somerharju, P., and Holthuis, J.C., J. Biol. Chem., 2007, vol. 282, pp. 17537–17547.Google Scholar
  24. 24.
    Maceyka, M., Harikumar, K.B., Milstein, S., and Spiegel, S., Trends Cell Biol., 2012, vol. 22, pp. 50–60.Google Scholar
  25. 25.
    Paul, P., Kamisaka, Y., Marks, D.L., and Pagano, R.E., J. Biol. Chem., 1996, vol. 271, pp. 2287–2293.Google Scholar
  26. 26.
    Seyfried, T.N. and Yu, R.K., Adv. Exp. Med. Biol., 1984, vol. 174, pp. 169–181.Google Scholar
  27. 27.
    Palestini, P., Masserini, M., Fiorilli, A., Calappi, E., and Tettamanti, G., J. Neurochem., 1993, vol. 61, pp. 955–960.Google Scholar
  28. 28.
    Sullards, M.C., Wang, E., Peng, Q., and Merrill, A.H., Jr., in Functional Lipidomics, Feng, L. and Prestwich, G.D., Eds., Salt Lake City: Echelon Biosciences, 2005, pp. 159–189.Google Scholar
  29. 29.
    Sullards, M.C., Wang, E., Peng, Q., and Merrill, A.H., Jr., Cell Mol. Biol., 2003, vol. 49, pp. 789–797.Google Scholar
  30. 30.
    Sullard, M.C., Methods Enzymol., 2000, vol. 312, pp. 32–45.Google Scholar
  31. 31.
    Merrill, A.H., Sullards, M.C., Allegood, J.C., Kelly, S., and Wang E., Methods, 2005, vol. 36, pp. 207–224.Google Scholar
  32. 32.
    Karlsson, K.A., Acta Chem. Scand., 1965, vol. 19, pp. 2425–2427.Google Scholar
  33. 33.
    Polito, A.J., Akita, T., and Sweeley, C.C., Biochemistry, 1968, vol. 7, pp. 2609–2614.Google Scholar
  34. 34.
    Sugiyama, E., Hara, A., Uemura, K., and Taketomi, T., Glycobiology, 1997, vol. 7, pp. 719–724.Google Scholar
  35. 35.
    Hunnam, V., Harvey, D.J., Priestman, D.A., Bateman, R.H., Bordoli, R.S., and Tyldesley, R.J., Am. Soc. Mass Spec., 2001, vol. 12, pp. 1220–1225.Google Scholar
  36. 36.
    Suzuki, M. and Suzuki, A., J. Biol. Chem., 2001, vol. 382, pp. 251–257.Google Scholar
  37. 37.
    O’Connor, P.B., Budnik, B.A., Ivleva, V.B., Kaur, P., Moyer, S.C., Pittman, J.L., and Costello, C.E., J. Am. Soc. Mass Spec., 2004, vol. 15, pp. 128–132.Google Scholar
  38. 38.
    Sugiura, Y., Shimma, S., Konishi, Y., Yamada, M.K., and Setou, M., PLoS ONE, 2008, vol. 3(9), e3232.Google Scholar
  39. 39.
    Adams, J. and Ann, Q., Mass. Spectrom. Rev., 1993, vol. 12, pp. 51–85.Google Scholar
  40. 40.
    Houjou, T., Yamatani, K., Nakanishi, H., Imagawa, M., Shinuzu, T., and Taguch, R., Rapid Commun. Mass Spectrom., 2004, vol. 18, pp. 3123–3130.Google Scholar
  41. 41.
    Domon, B., Vath, J.E., and Costello, C.E., Anal. Biochem., 1990, vol. 184, pp. 151–164.Google Scholar
  42. 42.
    Domon, B. and Costello, C.E., Biochemistry, 1998, vol. 27, pp. 1534–1543.Google Scholar
  43. 43.
    Futerman, A.N. and Hannun, Y.A., EMBO, 2004, vol. 5, pp. 777–782.Google Scholar
  44. 44.
    Han, X., Yang, J., Cheng, H., Ye, H., and Gross, R.W., Anal. Biochem., 2004, vol. 330, pp. 317–331.Google Scholar
  45. 45.
    Han, X., Yang K., Cheng, H., Fikes, K.N., and Gross, R.W., J. Lipid Res., 2005, vol. 46, pp. 1548–1560.Google Scholar
  46. 46.
    Masters, C.L., Simms, G., Weinman, N.F., Multhaup, G., McDonald, B.L., and Beyreuther, K., Proc. Natl. Acad. Sci. USA, 1985, vol. 82, pp. 4245–4249.Google Scholar
  47. 47.
    Walsh, D.M., Klyubin, I., Fadeeva, J.V., Rowan, M.J., and Selkoe, D.J., Biochem. Soc. Trans., 2002, vol. 30, pp. 552–557.Google Scholar
  48. 48.
    Eckert, G.P., Cairns, N.J., Maras, A., Gattas, W.F., and Muller, W.E., Dement. Geriatr. Cogn. Disord., 2000, vol. 11, pp. 181–186.Google Scholar
  49. 49.
    Choo-Smith, L.P. and Surewicz, W.K., FEBS Lett., 1997, vol. 402, pp. 95–98.Google Scholar
  50. 50.
    Agira, T., McDonald, M.P., and Yu, R.K., J. Lipid Res., 2008, vol. 49, pp. 1157–1175.Google Scholar
  51. 51.
    Yanagisava, K., Biochim. Biophys. Acta, 2007, vol. 1768, pp. 1943–1951.Google Scholar
  52. 52.
    Mahfoud, R., Garmy, N., Maresca, M., Yahi, N., Puigserver, A., and Fantini, J., J. Biol. Chem., 2002, vol. 277, pp. 11292–11296.Google Scholar
  53. 53.
    Yanagisava, K., Odaka, A., Suzuki, N., and Ihara, Y., Nat. Med., 1995, vol. 1, pp. 1062–1066.Google Scholar
  54. 54.
    Fantini, J., Garmy, N., Mahfoud, R., and Yahi, N., Exper. Rev. Mol. Med., 2002, vol. 4, pp. 1–22.Google Scholar
  55. 55.
    Vetrivel, K.S. and Thinakaran, G., Biochim. Biophys. Acta, 2010, vol. 1801, pp. 860–867.Google Scholar
  56. 56.
    Soderberg, M., Edlund, C., Alafuzoff, I., Kristensson, K., and Dallner, G., J. Neurochem., 1992, vol. 59, pp. 1646–1653.Google Scholar
  57. 57.
    Shepardson, N.E., Shankar, G.M., and Selkoe, D.J., Arch. Neurol., 2011, vol. 68, pp. 1385–1392.Google Scholar
  58. 58.
    Cutler, R.G., Kelly, J., Storie, K., Pedersen, W.A., Tammara, A., Hatanpaa, K., et al., Proc. Natl. Acad. Sci. USA, 2004, vol. 101, pp. 2070–2075.Google Scholar
  59. 59.
    He, X., Huang, Y., Li, B., Gong, C.X., and Schuchman, E.H., Neurobiology of Aging, 2010, vol. 31, pp. 398–408.Google Scholar
  60. 60.
    Bornemann, K.D. and Staufenbiel, M., Ann. NY Acad. Sci., 2007, vol. 908, pp. 260–266.Google Scholar
  61. 61.
    Benedikz, E., Kloskowska, E., and Winblad, B., J. Cell Mol. Med., 2009, vol. 13, pp. 1034–1042.Google Scholar
  62. 62.
    Stepanichev, M.Y., Moiseeva, Y.V., Lazareva, N.A., and Gulyaeva, N.V., Neurosci. Behav. Physiol., 2005, vol. 35, pp. 511–518.Google Scholar
  63. 63.
    Ostrovskaya, R.U., Bel’nik, A.P., and Storozheva, Z.I., Byul. Eksper. Biol. Med., 2008, vol. 146, pp. 84–88.Google Scholar
  64. 64.
    Alessenko, A.V., Bugrova, A.E., and Dudnik, L.B., Biochem. Soc. Trans., 2004, vol. 32, pp. 144–146.Google Scholar
  65. 65.
    Nesterova, I.V., Bobkova, N.V., Medvinskaya, N.I., Samokhin, A.N., and Aleksandrova, I., Morfologiya, 2007, vol. 131, pp. 32–36.Google Scholar
  66. 66.
    Barrier, L., Ingard, S., Fauconneau, B., and Hage, G., Neurobiol. Aging, 2010, vol. 31, pp. 1843–1853.Google Scholar
  67. 67.
    de Chaves, E.P., Bussiere, M., MacInnis, B., Vance, D.E., Campeton, R.B, and Vance, J.E., J. Biol. Chem., 2001, vol. 276, pp. 36207–36217.Google Scholar
  68. 68.
    Obeid, L.M., Lenardic, C.M., Karolak, L.A., and Hannun, Y.A., Science, 1993, vol. 259, pp. 1769–1771.Google Scholar
  69. 69.
    Lee, J.-T., Xu, J., Ku, G., Han, X., Yang, D.-I., Chen, S., Buccoliero, R., and Futterman, A.H., Pharmacological Res., 2003, vol. 47, pp. 409–419.Google Scholar
  70. 70.
    Beal, M.F., Ann. Neurol., 2005, vol. 58, pp. 495–505.Google Scholar
  71. 71.
    Yanagisawa, K., Biochim. Biophys. Acta, 2007, vol. 1768, pp. 1943–1951.Google Scholar
  72. 72.
    Ariga, T., Yanagisawa, M., Wakade, C., Ando, S., Buccafusco, J., McDonald, M.P., and Yu, R.K., ASN Neuro., 2010, vol. 2, no. 4, p. e00044.Google Scholar
  73. 73.
    Jana, A. and Pahan, K., J. Neurosci., 2010, vol. 30, pp. 12676–12689.Google Scholar
  74. 74.
    Lee, J.-T., Xu, J., Lee, J.-M., Ku, G., Han, X., Yang, D.-I., Chen, S., and Hsu, C.Y., J. Cell Biol., 2004, vol. 164, pp. 123–131.Google Scholar
  75. 75.
    Yang, D.-I., Yeh, C.-H., Chen, S., Xu, J., and Hsu, C.Y., Neurobiol. Dis., 2004, vol. 17, pp. 99–107.Google Scholar
  76. 76.
    Malaplate-Armand, C., Florent-Böchard, S., Youssef, I., Koziel, V., Sponne, I., Kriem, B., Leininger-Muller, B., Olivier, J.L., Oster, T., and Pillot, T., Neurobiol. Dis., 2006, vol. 23, pp. 178–189.Google Scholar
  77. 77.
    Xuan, N.T., Shumilina, E., Kempe, D.S., Gulbins, E., and Lang, F., J. Neuroimmunol., 2010, vol. 219, pp. 81–89.Google Scholar
  78. 78.
    Zeng, C., Lee, J.T., Chen, S., Hsu, C.Y., and Xu, J., J. Neurochem., 2005, vol. 94, pp. 703–712.Google Scholar
  79. 79.
    Chen, S., Lee, J.M., Zeng, C., Chen, H., Hsu, C.Y., and Xu, J., J. Neurochem., 2006, vol. 97, pp. 631–640.Google Scholar
  80. 80.
    Malaplate-Armand, C., Florent-Bechard, S., Youssef, I., Koziel, V., Sponne, I., Kriem, B., Leininger-Muller, D., Olivier, J.-L., Jster, T., and Pillot, T., Neurobiol. Dis., 2006, vol. 23, pp. 178–189.Google Scholar
  81. 81.
    He, X., Huang, Y., Li, B., and Schuchman, E.H., Neurobiol. Aging, 2010, vol. 31, pp. 398–408.Google Scholar
  82. 82.
    Fillipov, V., Song, M.A., Zhang, K., Vinters, H.V., Tung, S., Kirsh, W.M., Yang, J., and Duerksen-Hughes, P.J., J. Alzheimers Dis., 2012, vol. 29, pp. 537–547.Google Scholar
  83. 83.
    Pettegrew, J.W., Panchalingham, K., Hamilton, R.L., and McClure, R.J., Neurochem. Res., 2001, vol. 26, pp. 771–782.Google Scholar
  84. 84.
    Chan, R.B., Oliveira, T.G., Cortes, E.P., Honig, L.S., Duff, K.E., Small, S.A., Wenk, M.R., Shui, G., and Di Paolo, G., J. Biol. Chem., 2012, vol. 287, pp. 2678–2688.Google Scholar
  85. 85.
    Bandaru, V.V., Troncoso, J., Wheeler, D., Pletnikova, O., Wang, J., and Connant, K., Neurobiol. Aging, 2009, vol. 30, pp. 591–599.Google Scholar
  86. 86.
    Han, X., Holtzman, D., McKeel, D.W., Jr., Kelly, J., and Morris, J.C., J. Neurochem., 2002, vol. 82, pp. 809–818.Google Scholar
  87. 87.
    Jana, A, Hogan, E.L., and Pahan, K., J. Neurol. Sci., 2009, vol. 278, pp. 5–15.Google Scholar
  88. 88.
    Jana, A. and Pahan, K., J. Biol. Chem., 2004, vol. 279, pp. 51451–51459.Google Scholar
  89. 89.
    Lee, J.-T., Xu, J., Ku, G., Han, X., Yang, D.-I., Chen, S., and Hs, C.Y., J. Cell Biol., 2004, vol. 164, pp. 123–131.Google Scholar
  90. 90.
    Shupik, M.A., Vanin, A.F., and Alessenko, A.V., Biochemistry (Moscow), 2011, vol. 76, pp. 1197–1209.Google Scholar
  91. 91.
    Dobrowsky, R.T., Werner, M.H., Castellino, A.M., Cao, M.V., and Hannun, Y.A., Science, 1994, vol. 265, pp. 1596–1599.Google Scholar
  92. 92.
    Yu, Z.F., Nikolaeva-Karakashian, M., Zhou, D., Cheng, G., Schuchman, E.H., and Mattson, M.P., J. Mol. Neurosci., 2000, vol. 15, pp. 85–97.Google Scholar
  93. 93.
    Reddy, P.H., CNS Spectr., 2009, vol. 14, pp. 8–18.Google Scholar
  94. 94.
    Gottfries, C.G., Karkson, I., and Svennerholm, L., Int. Psychogeriatr., 1996, vol. 8, pp. 365–372.Google Scholar
  95. 95.
    Zhang, S.C. and Duncan, I.D., Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 4086–4094.Google Scholar
  96. 96.
    Katsel, P., Li, C., and Haroutunian, V., Neurochem. Res., 2007, vol. 32, pp. 845–856.Google Scholar
  97. 97.
    Arenc, C., Cell. Physiol. Biochem., 2010, vol. 26, pp. 1–8.Google Scholar
  98. 98.
    Kornburger, J., Tripal, P., Reichel, M., Muhle, C., Rhein, C., Muehbacher, M., Groemer, T.W., and Gulbins, E., Cell. Physiol. Biochem., 2010, vol. 26, pp. 9–20.Google Scholar
  99. 99.
    Taguchi, M., Sugimoto, K., Akama, T., Yamamoto, K., Suzuki, T., Tomishima, Y., Nishiguchi, M., Arai, K., Takanashi, K., and Kobori, T., Bioorg. Med. Chem. Lett., 2003, vol. 13, pp. 1963–1966.Google Scholar
  100. 100.
    Huang, Y., Tanimukai, H., Liu, F., Igbal, K., Grundke-Igbal, I., and Gong, C.X., Eur. J. Neurosci., 2004, vol. 20, pp. 3489–3497.Google Scholar
  101. 101.
    Park, J.H. and Schuchman, E.H., Biochim. Biophys. Acta, 2006, vol. 1758, pp. 2133–2138.Google Scholar
  102. 102.
    Han, X., Fagan, A.M., Cheng, H., Morris, J.C., Xiong, C., and Holtzman, D.M., Ann. Neurol., 2003, vol. 54, pp. 115–119.Google Scholar
  103. 103.
    Satoi, H., Tomimoto, H., Ohtani, R., Kitano, T., Kondo, T., Watanabe, M., et al., Neuroscience, 2005, vol. 130, pp. 657–666.Google Scholar
  104. 104.
    Mielke, M.M., Haughey, N.J., Bandaru, V.V., Weinberg, D.D., Darby, E., Zaidi, N., and Pavlik, V., J. Alzheimer’s Dis., 2011, vol. 27, pp. 259–269.Google Scholar
  105. 105.
    Kosicek, M., Zetterberg, H., Andreasen, N., PeterKatalinic, J., and Hecimovic, S., Neurosci. Lett., 2012, vol. 516, pp. 302–305.Google Scholar
  106. 106.
    Mielke, M.M., Hauhey, N.J., Bandaru, V.V., Schech, S., Carrick, R., Carlson, M.C., Mori, S., Miller, M.I., Ceritoglu, C., Brown, T., Albert, M., and Lyketsos, C.G., Alzheimers Diment., 2010, vol. 6, pp. 378–385.Google Scholar
  107. 107.
    Han, X., Rozen, S., Boyle, S.H., Hellegers, C., Cheng, H., Burke, J.R., Welsh-Bohmer, KA., Doraiswamym, P.M., and Kaddurah-Dauk, R. PLoS One, 2011, vol. 6, no. 7, e21643.Google Scholar
  108. 108.
    Karatasso, Yu.O., Sullard, K., Fedorova, Ya.B., Korotaeva, A.A., Gavrilova, S.S., Varfolomeev, S.D., and Alessenko, A.V., Mass Spektr., 2008, vol. 5, pp. 106–116.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2013

Authors and Affiliations

  1. 1.Emanuel Institute of Biochemical Physics of the Russian Academy of SciencesMoscowRussia

Personalised recommendations