Neurochemical Research

, Volume 26, Issue 7, pp 771–782 | Cite as

Brain Membrane Phospholipid Alterations in Alzheimer's Disease

  • Jay W. Pettegrew
  • Kanagasabai Panchalingam
  • Ronald L. Hamilton
  • Richard J. McClure
Article

Abstract

Studies have demonstrated alterations in brain membrane phospholipid metabolite levels in Alzheimer's disease (AD). The changes in phospholipid metabolite levels correlate with neuropathological hallmarks of the disease and measures of cognitive decline. This 31P nuclear magnetic resonance (NMR) study of Folch extracts of autopsy material reveals significant reductions in AD brain levels of phosphatidylethanolamine (PtdEtn) and phosphatidylinositol (PtdIns), and elevations in sphingomyelin (SPH) and the plasmalogen derivative of PtdEtn. In the superior temporal gyrus, there were additional reductions in the levels of diphosphatidylglycerol (DPG) and phosphatidic acid (PtdA). The findings are present in 3/3 as well as 3/4 and 4/4 apolipoprotein E (apoE) genotypes. The AD findings do not appear to reflect non-specific neurodegeneration or the presence of gliosis. The present findings could possibly contribute to an abnormal membrane repair in AD brains which ultimately results in synaptic loss and the aggregation of Aβ peptide.

Phospholipid metabolism Alzheimer's disease apolipoprotein E 31P NMR phosphatidylethanolamine phosphatidylethanolamine plasmalogen phosphatidylinositol sphingomyelin diphosphatidylglycerol 

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REFERENCES

  1. 1.
    Pettegrew, J. W., Minshew, N. J., Cohen, M. M., Kopp, S. J., and Glonek, T. 1984. P-31 NMR changes in Alzheimer's and Huntington's disease brain (abstract). Neurology 34(Suppl 1):281.Google Scholar
  2. 2.
    Pettegrew, J. W., Withers, G., Panchalingam, K., and Post, J. F. 1987. 31P nuclear magnetic resonance (NMR) spectroscopy of brain in aging and Alzheimer's disease. J. Neural Transm. Suppl. 24:261–268.Google Scholar
  3. 3.
    Pettegrew, J. W., Moossy, J., Withers, G., McKeag, D., and Panchalingam, K. 1988. 31P Nuclear Magnetic Resonance study of the brain in Alzheimer's disease. J. Neuropathol. Exp. Neurol. 47:235–248.Google Scholar
  4. 4.
    Brown, G. G., Levine, S. R., Gorell, J. M., Pettegrew, J. W., Gdowski, J. W., Bueri, J. A., Helpern, J. A., and Welch, K. M. 1989. In vivo 31P NMR profiles of Alzheimer's disease and multiple subcortical infarct dementia. Neurology 39:1423–1427.Google Scholar
  5. 5.
    Nitsch, R. M., Blusztajn, J. K., Pittas, A. G., Slack, B. E., Growdon, J. H., and Wurtman, R. J. 1992. Evidence for a membrane defect in Alzheimer disease brain. Proc. Natl. Acad. Sci. USA 89:1671–1675.Google Scholar
  6. 6.
    Smith, C. D., Gallenstein, L. G., Layton, W. J., Kryscio, R. J., and Markesbery, W. R. 1993. 31P magnetic resonance spectroscopy in Alzheimer's and Pick's disease. Neurobiol. Aging 14:85–92.Google Scholar
  7. 7.
    Cuenod, C.-A., Kaplan, D. B., Michot, J.-L., Jehenson, P., Leroy-Willig, A., Forette, F., Syrota, A., and Boller, F. 1995. Phospholipid abnormalities in early Alzheimer's disease. Arch. Neurol. 52:89–94.Google Scholar
  8. 8.
    Pettegrew, J. W., Panchalingam, K., Klunk, W. E., McClure, R. J., and Muenz, L. R. 1994. Alterations of cerebral metabolism in probable Alzheimer's disease: A preliminary study. Neurobiol. Aging 15:117–132.Google Scholar
  9. 9.
    Klunk, W. E., Panchalingam, K., McClure, R. J., and Pettegrew, J. W. 1996. Quantitative 1H and 31P MRS of PCA extracts of postmortem Alzheimer's disease brain. Neurobiol. Aging 17:349–357.Google Scholar
  10. 10.
    Pettegrew, J. W., Panchalingam, K., Withers, G., McKeag, D., and Strychor, S. 1990. Changes in brain energy and phospholipid metabolism during development and aging in the Fischer 344 rat. J. Neuropathol. Exp. Neurol. 49:237–249.Google Scholar
  11. 11.
    Vance, D. E. 1991. Phospholipid metabolism and cell signalling in eucaryotes. Pages 205–240, in Vance, D. E., and Vance, J. (eds.), Biochemistry of lipids, lipoproteins and membranes, Volume 20, Elsevier, New York.Google Scholar
  12. 12.
    Pettegrew, J. W., McClure, R. J., Keshavan, M. S., Minshew, N. J., Panchalingam, K., and Klunk, W. E. 1997. 31P magnetic resonance spectroscopy studies of developing brain. Pages 71–92, in Keshavan, M. S., and Murray, R. M. (eds.), Neurodevelopement & Adult Psychopathology, Cambridge University Press, Cambridge.Google Scholar
  13. 13.
    Geddes, J. W., Panchalingam, K., Keller, J. N., and Pettegrew, J. W. 1997. Elevated phosphocholine and phosphatidyl choline following rat entorhinal cortex lesions. Neurobiol. Aging 18:305–308.Google Scholar
  14. 14.
    Kanfer, J. N., Pettegrew, J. W., Moossy, J., and McCartney, D. G. 1993. Alterations of selected enzymes of phospholipid metabolism in Alzheimer's disease brain tissue as compared to non-Alzheimer's disease controls. Neurochem. Res. 18:331–334.Google Scholar
  15. 15.
    Pettegrew, J. W., Panchalingam, K., Moossy, J., Martinez, J., Rao, G., and Boller, F. 1988. Correlation of phosphorus-31 magnetic resonance spectroscopy and morphologic findings in Alzheimer's disease. Arch. Neurol. 45:1093–1096.Google Scholar
  16. 16.
    Klunk, W. E., Xu, C. J., McClure, R. J., Panchalingam, K., Stanley, J. A., and Pettegrew, J. W. 1997. Aggregation of β-amyloid peptide is promoted by membrane phospholipid metabolites elevated in Alzheimer's disease brain. J. Neurochem. 69:266–272.Google Scholar
  17. 17.
    Pettegrew, J. W., Klunk, W. E., Kanal, E., Panchalingam, K., and McClure, R. J. 1995. Changes in brain membrane phospholipid and high-energy phosphate metabolism precede dementia. Neurobiol. Aging 16:973–975.Google Scholar
  18. 18.
    Pettegrew, J. W., Klunk, W. E., Panchalingam, K., McClure, R. J., and Stanley, J. A. 1997. Magnetic resonance spectroscopic changes in Alzheimer's disease. Ann. NY Acad. Sci. 826:282–306.Google Scholar
  19. 19.
    Mason, R. P., Shoemaker, W. J., Shajenko, L., Chambers, T. E., and Herbette, G. 1992. Structural changes in Alzheimer's disease brain membrane mediated by alteration in cholesterol. Neurobiol. Aging 13:413–419.Google Scholar
  20. 20.
    Mahley, R. W. 1988. Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science 240:622–630.Google Scholar
  21. 21.
    Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L.-H. 1999. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622.Google Scholar
  22. 22.
    Aronson, M. K., Ooi, W. L., Morgenstern, H., Hafner, M. S., Masur, D., and Crystal H. 1990. Women, myocardial infraction, and dementia in the very old. Neurology 40:1102–1106.Google Scholar
  23. 23.
    Sparks, D. L., Hunsaker, J. C., III, Scheff, S. W., Kryscio, R. J., Henson, J. L., and Markesbery, W. R. 1990. Cortical senile plaques in coronary artery diseases, aging and Alzheimer's disease. Neurobiol. Aging 11:601–607.Google Scholar
  24. 24.
    Khachaturian, Z. S. 1985. Diagnosis of Alzheimer's disease. Arch. Neurol. 42:1097–1105.Google Scholar
  25. 25.
    Moossy, J., Zubenko, G., Martinez, J., Rao, G. R., Kopp, U., and Hanin, I. 1988. Bilateral symmetry of morphologic lesions in Alzheimer's disease. Arch. Neurol. 45:251–254.Google Scholar
  26. 26.
    Meneses, P. and Glonek, T. 1988. High resolution 31P NMR of extracted phospholipids. J. Lipid Res. 29:679–690.Google Scholar
  27. 27.
    Pettegrew, J. W., Panchalingam, K., Levine, J., McClure, R. J., Gershon, S., and Yao, J. K. 2001. Chronic myo-inositol increases rat brain phosphatidylethanolamine plasmalogen. Biol. Psychiatry 49:444–453.Google Scholar
  28. 28.
    Steel, R. G. D. and Torrie, J. H. 1980. Principles and Procedures of Statistics a Biometrical Approach, McGraw-Hill, New York.Google Scholar
  29. 29.
    Klunk, W. E., Xu, C. J., Panchalingam, K., McClure, R. J., and Pettegrew, J. W. 1994. Analysis of magnetic resonance spectra by mole percent: Comparison to absolute units. Neurobiol. Aging 15:133–140.Google Scholar
  30. 30.
    Simons, K. and Ikonen, E. 1997. Functional rafts in cell membranes. Nature 387:569–572.Google Scholar
  31. 31.
    Harder, T. and Simons, K. 1997. Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains. Curr. Opinion Cell Biol. 9:534–542.Google Scholar
  32. 32.
    Pettegrew, J. W., Klunk, W. E., Panchalingam, K., McClure, R. J., and Stanley, J. A. 2000. Molecular insights into neurodevelopmental and neurodegenerative diseases. Brain Res. Bull. 53:455–469.Google Scholar
  33. 33.
    Maulik, P. R. and Shipley, G. G. 1996. Interactions of N-stearoyl sphingomyelin with cholesterol and dipalmitoylphosphatidylcholine in bilayer membranes. Biophys. J. 70:2256–2265.Google Scholar
  34. 34.
    Scott, H. L., Jakobsson, E., Mashl, J., and Chiu, S.-W. 2001. Combined molecular dynamics and Monte Carlo simulation of sphingomyelin lipid bylayers (abstract). Biophys. J. 80(Suppl):525a.Google Scholar
  35. 35.
    Ballou, L. R., Laulederkind, S. J., Rosloniec, E. F., and Raghow, R. 1996. Ceramide signalling and the immune response. Biochim. Biophys. Acta 1301:273–287.Google Scholar
  36. 36.
    Pyne, S., Tolan, D. G., Conway, A. M., and Pyne, N. 1997. Sphingolipids as differential regulators of cellular signalling processes. Biochem. Soc. Trans. 25:549–556.Google Scholar
  37. 37.
    Haimovitz-Friedman, A., Kolesnick, R. N., and Fuks, Z. 1997. Ceramide signaling in apoptosis. Br. Med. Bull. 53:539–553.Google Scholar
  38. 38.
    Perry, D. K. and Hannun, Y. A. 1998. The role of ceramide in cell signaling. Biochim. Biophys. Acta 1436:233–243.Google Scholar
  39. 39.
    Merrill, A. H. J., Morgan, E. T., Nikolova-Karakashian, M., and Stewart, J. 1999. Sphingomyelin hydrolysis and regulation of the expression of the gene for cytochrome P450. Biochem. Soc. Trans. 27:383–387.Google Scholar
  40. 40.
    Levade, T. and Jaffrezou, J. P. 1999. Signalling sphingomyelinases: which, where, how and why? Biochim. Biophys. Acta 1438:1–17.Google Scholar
  41. 41.
    Hannun, Y. A. and Luberto, C. 2000. Ceramide in the eukaryotic stress response. Trends Cell Biol. 10:73–80.Google Scholar
  42. 42.
    Gross, R. W. 1984. High plasmalogen and arachidonic acid content of canine myocardial sarcolemma: a fast atom bombardment mass spectroscopic and gas chromatography-mass spectroscopic characterization. Biochemistry 23:158–165.Google Scholar
  43. 43.
    Diagne, A., Fauvel, J., Record, M., Chap, H., and Douste-Blazy, L. 1984. Studies on ether phospholipids II. Comparative composition of various tissues from human, rat and guinea pig. Biochim. Biophys. Acta 793:221–231.Google Scholar
  44. 44.
    Lohner, K., Balgavy, P., Hermetter, A., Paltauf, F., and Laggner, P. 1991. Stabilization of non-bilayer structures by the etherlipid ethanolamine plasmalogen. Biochim. Biophys. Acta 1061:132–140.Google Scholar
  45. 45.
    Ginsberg, L., Xuereb, J. H., and Gershfeld, N. L. 1998. Membrane instability, plasmalogen content, and Alzheimer's disease. J. Neurochem. 70:2533–2538.Google Scholar
  46. 46.
    Kaufman, A. E., Goldfine, H., Narayan, O., and Gruner, S. M. 1990. Physical studies on the membranes and lipids of plasmalogen-deficient Megasphaera elsdenii. Chem. Phys. Lipids 55:41–48.Google Scholar
  47. 47.
    Lohner, K. 1996. Is the high propensity of ethanolamine plasmalogens to form non-lamellar lipid structures manifested in the properties of biomembranes? Chem. Phys. Lipids 81: 167–184.Google Scholar
  48. 48.
    Glaser, P. E. and Gross, R. W. 1994. Plasmenylethanolamine facilitates rapid membrane fusion: a stopped-flow kinetic investigation correlating the propensity of a major plasma membrane constituent to adopt an HII phase with its ability to promote membrane fusion. Biochemistry 33:5805–5812.Google Scholar
  49. 49.
    Farooqui, A. A., Rapoport, S. I., and Horrocks, L. A. 1997. Membrane phospholipid alterations in Alzheimer's disease: deficiency of ethanolamine plasmalogens. Neurochem. Res. 22: 523–527.Google Scholar
  50. 50.
    Schu, P. V., Takegawa, K., Fry, M. J., Stack, J. H., Waterfield, M. D., and Emr, S. D. 1993. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260:88–91.Google Scholar
  51. 51.
    Qiao, L., Nan, F., Kunkel, M., Gallegos, A., Powis, G., and Kozikowski, A. P. 1998. 3-Deoxy-D-myo-inositol 1-phosphate, 1-phosphonate, and ether lipid analogues as inhibitors of phosphatidylinositol-3-kinase signaling and cancer cell growth. J. Med. Chem. 41:3303–3306.Google Scholar
  52. 52.
    Merrill, A. H. J. and Schroeder, J. J. 1993. Lipid modulation of cell function. Annu. Rev. Nutr. 13:539–559.Google Scholar
  53. 53.
    Turini, M. E. and Holub, B. J. 1994. The cleavage of plasmenylethanolamine by phospholipase A2 appears to be mediated by the low affinity binding site of the TxA2/PGH2 receptor in U46619-stimulated human platelets. Biochim. Biophys. Acta 1213:21–26.Google Scholar
  54. 54.
    Gross, R. W. 1985. Identification of plasmalogen as the major phospholipid constituent of cardiac sarcoplasmic reticulum. Biochemistry 24:1662–1668.Google Scholar
  55. 55.
    Paltauf, F. 1994. Ether lipids in biomembranes. Chem. Phys. Lipids 74:101–139.Google Scholar
  56. 56.
    Yavin, E. and Gatt, S. 1972. Oxygen-dependent cleavage of the vinyl-ether linkage of plasmologens. 1. Cleavage by rat-brain supernatant. Eur. J. Biochem. 25:431–436.Google Scholar
  57. 57.
    Reiss, D., Beyer, K., and Engelmann, B. 1997. Delayed oxidative degradation of polyunsaturated diacyl phospholipids in the presence of plasmalogen phospholipids in vitro. Biochem. J. 323:807–814.Google Scholar
  58. 58.
    Engelmann, B., Brautigam, C., and Thiery, J. 1994. Plasmalogen phospholipids as potential protectors against lipid peroxidation of low density lipoproteins. Biochem. Biophys. Res. Commun. 204:1235–1242.Google Scholar
  59. 59.
    Farooqui, A. A., Yang, H. C., and Horrocks, L. A. 1995. Plasmalogens, phospholipases A2 and signal transduction. Brain Res. Brain Res. Rev. 21:152–161.Google Scholar
  60. 60.
    Holub, B. J. 1986. Metabolism and function of myo-inositol and inositol phospholipids. Annu. Rev. Nutr. 6:563–597.Google Scholar
  61. 61.
    Klunk, W. E., Panchalingam, K., McClure, R. J., Stanley, J. A., and Pettegrew, J. W. 1998. Metabolic alterations in postmortem Alzheimer's disease brain are exaggerated by Apo-E4. Neurobiol. Aging 19:511–515.Google Scholar
  62. 62.
    Schlame, M., Rua, D., and Greenberg, M. L. 2000. The biosynthesis and functional role of cardiolipin. Prog. Lipid Res. 39:257–288.Google Scholar
  63. 63.
    Lehninger, A. L., Nelson, D. L., and Cox, M. M. 1993. Principles of Biochemistry, Worth Publishers, New York.Google Scholar
  64. 64.
    Jope, R. S., Song, L., and Powers, R. E. 1997. Cholinergic activation of phosphoinositide signaling is impaired in Alzheimer's disease brain. Neurobiol. Aging 18:111–120.Google Scholar
  65. 65.
    Fowler, C. J. 1997. The role of the phosphoinositide signalling system in the pathgenesis of sporadic Alzheimer's disease: a hypothesis. Brain Res. Rev. 25:373–380.Google Scholar
  66. 66.
    McAuley, K. E., Fyfe, P. K., Ridge, J. P., Isaacs, N. W., Cogdell, R. J., and Jones, M. R. 1999. Structural details of an interaction between cardiolipin and an integral membrane protein. Proc. Natl. Acad. Sci. USA 96:14706–14711.Google Scholar
  67. 67.
    Robinson, N. C. 1993. Functional binding of cardiolipin to cytochrome c oxidase. J. Bioenerg. Biomembr. 25:153–163.Google Scholar
  68. 68.
    Kish, S., Bergeron, C., Rajput, A., Dozic, S., Mastrogracosno, F., Chong, L. J., Wilson, J. M., DiStefano, L. M., and Nobregia, J. N. 1992. Brain cytochrome oxidase in Alzheimer's disease. J. Neurochem. 59:776–779.Google Scholar
  69. 69.
    Sims, N. R., Finegan, J. M., Blass, J. P., Bowen, D. M., and Neary, D. 1987. Mitochondrial function in brain tissue in primary degenerative dementia. Brain Res. 436:30–38.Google Scholar
  70. 70.
    Chauhan, A., Ray. I., and Chauhan, V. P. S. 2000. Interaction of amyloid beta-protein with anionic phospholipids: Possible involvement of Lys28 and C-terminus aliphatic amino acids. Neurochem. Res. 25:423–429.Google Scholar
  71. 71.
    Vance, J. E., Campenot, R. B., and Vance, D. E. 2000. The synthesis and transport of lipids of axonal growth and nerve regeneration. Biochim. Biophys. Acta 1486:84–96.Google Scholar
  72. 72.
    Hirokawa, N. 1998. Kinesin and dynein superfamily proteins and teh mechanism of organelle transport. Science 279:519–526.Google Scholar
  73. 73.
    Ginsberg, L., Rafique, S., Xuereb, J. H., Rapoport, S. I., and Gershfeld, N. L. 1995. Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer's disease brain. Brain Res. 698:223–226.Google Scholar
  74. 74.
    Prasad, M. R., Lovell, M. A., Yatin, M., Dhillon, H., and Markesbery, W. R. 1998. Regional membrane phospholipid alterations in Alzheimer's disease. Neurochem. Res. 23:81–88.Google Scholar
  75. 75.
    Wells, K., Farooqui, A. A., Liss, L., and Horrocks, L. A. 1995. Neural membrane phospholipids in Alzheimer disease. Neurochem. Res. 20:1329–1333.Google Scholar
  76. 76.
    Guan, Z., Wang, Y., Cairns, N. J., Lantos, P. L., Dallner, G., and Sindelar, P. J. 1999. Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease. J. Neuropathol. Exp. Neurol. 58:740–747.Google Scholar
  77. 77.
    McIlwain, H. and Bachelard, H. S. 1985. Biochemistry and the Central Nervous System, Churchill Livingstone, Edinburgh.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Jay W. Pettegrew
    • 1
    • 2
    • 4
  • Kanagasabai Panchalingam
    • 5
  • Ronald L. Hamilton
    • 3
  • Richard J. McClure
    • 5
  1. 1.Neurophysics LaboratoryDepartment of PsychiatryUSA
  2. 2.Department of NeurologyUSA
  3. 3.Department of Pathology (Division of Neuropathology), School of MedicineUniversity of PittsburghPittsburgh
  4. 4.Health Services AdministrationUniversity of PittsburghPittsburgh
  5. 5.Neurophysics Laboratory, Department of PsychiatryUniversity of PittsburghPittsburgh

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