Lipidomic Analysis of Postmortem Prefrontal Cortex Phospholipids Reveals Changes in Choline Plasmalogen Containing Docosahexaenoic Acid and Stearic Acid Between Cases With and Without Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive and incurable brain disorder that has been associated with structural changes in brain phospholipids (PLs), including diacyl species and ether-linked PLs known as plasmalogens. Most studies have characterized total changes in brain PL pools (e.g., choline plasmalogens), particularly in prefrontal cortex, but detailed and quantitative information on the molecular PL species impacted by the disease is limited. In this study, we used a comprehensive mass-spectrometry method to quantify diacyl and plasmalogen species, alkyl synthetic precursors of plasmalogens, and lysophospholipid degradation products of diacyl and plasmalogen PLs, in postmortem samples of prefrontal cortex from 21 AD patients and 20 age-matched controls. Total PLs were also quantified with gas-chromatography analysis of bound fatty acids following thin layer chromatography isolation. There was a significant 27% reduction in the concentration (nmol/g wet weight) of choline plasmalogen containing stearic acid (alkenyl group) and docosahexaenoic acid in AD compared to controls. Stearic acid concentration in total PLs was reduced by 26%. Our findings suggest specific changes in PLs containing stearic acid and docosahexaenoic acid in AD prefrontal cortex, highlighting structural and turnover PL pathways that could be targeted.

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Abbreviations

AD:

Alzheimer’s disease

BHT:

Butylated hydroxytoluene

CV:

Coefficient of variation

DHA:

Docosahexaenoic acid

DHAP:

Dihydroxyacetonephosphate

EDTA:

Ethylenediaminetetraacetic acid

GC:

Gas-chromatography

HPLC:

High-performance liquid chromatography

Lyso PakCho:

1-alkyl-2-hydroxy phosphatidylcholine

Lyso PtdCho:

Lyso phsphatidylcholine

Lyso PakEtn:

1-alkyl-2-hydroxy phosphatidylethanolamine

Lyso PtdEtn:

Lyso phosphatidylethanolamine

Lyso PlsCho:

Lyso plasmenylcholine

Lyso PlsEtn:

Lyso plasmenylethanolamine

PakCho:

Alkyl-acyl phosphatidylcholine

PakEtn:

Alkyl-acyl phosphatidylethanolamine

PtdCho:

Diacyl phosphatidylcholine

PtdEtn:

Diacyl phosphatidylethanolamine

PLs:

Phospholipids

PlsCho:

Choline plasmalogens

PlsEtn:

Ethanolamine plasmalogens

PMI:

Postmortem interval

PUFAs:

Polyunsaturated fatty acids

Sn:

Stereospecifically numbered

TLC:

Thin layer chromatography

UPLC-MS/MS:

Ultra-high-performance liquid chromatography tandem mass-spectrometry

References

  1. Alzheimer’s Disease International. (2019). World Alzheimer Report 2019: Attitudes to dementia. London: Alzheimer’s Disease International.

    Google Scholar 

  2. Andersson, D. A., Nash, M., & Bevan, S. (2007). Modulation of the cold-activated channel TRPM8 by lysophospholipids and polyunsaturated fatty acids. Journal of Neuroscience, 27(12), 3347–3355. https://doi.org/10.1523/JNEUROSCI.4846-06.2007.

    CAS  Article  PubMed  Google Scholar 

  3. Berg, L., McKeel, D. W., Jr., Miller, J. P., Storandt, M., Rubin, E. H., Morris, J. C., et al. (1998). Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: Relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Archives of Neurology, 55(3), 326–335. https://doi.org/10.1001/archneur.55.3.326.

    CAS  Article  PubMed  Google Scholar 

  4. Braak, H., & Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica, 82(4), 239–259. https://doi.org/10.1007/BF00308809.

    CAS  Article  PubMed  Google Scholar 

  5. Cheon, Y., Kim, H. W., Igarashi, M., Modi, H. R., Chang, L., Ma, K., et al. (2012). Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A(2)-VIA (iPLA(2)beta)-knockout mice. Biochimica et Biophysica Acta, 1821(9), 1278–1286. https://doi.org/10.1016/j.bbalip.2012.02.003.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Dugger, B. N., & Dickson, D. W. (2017). Pathology of neurodegenerative diseases. Cold Spring Harbor Perspectives in Biology. https://doi.org/10.1101/cshperspect.a028035.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dugger, B. N., & Taha, A. Y. (2020). Measuring peripheral markers of neuroinflammation in Alzheimer’s disease—Challenges and opportunities. Brain, Behavior, and Immunity, 88, 840–841. https://doi.org/10.1016/j.bbi.2020.06.004.

    Article  PubMed  Google Scholar 

  8. Esposito, G., Giovacchini, G., Liow, J. S., Bhattacharjee, A. K., Greenstein, D., Schapiro, M., et al. (2008). Imaging neuroinflammation in Alzheimer’s disease with radiolabeled arachidonic acid and PET. Journal of Nuclear Medicine, 49(9), 1414–1421. https://doi.org/10.2967/jnumed.107.049619.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Fahy, E., Subramaniam, S., Brown, H. A., Glass, C. K., Merrill, A. H., Jr., Murphy, R. C., et al. (2005). A comprehensive classification system for lipids. Journal of Lipid Research, 46(5), 839–861. https://doi.org/10.1194/jlr.E400004-JLR200.

    CAS  Article  PubMed  Google Scholar 

  10. Filshtein, T. J., Dugger, B. N., Jin, L. W., Olichney, J. M., Farias, S. T., Carvajal-Carmona, L., et al. (2019). Neuropathological diagnoses of demented Hispanic, Black, and non-Hispanic White decedents seen at an Alzheimer’s Disease Center. Journal of Alzheimer’s Disease, 68(1), 145–158. https://doi.org/10.3233/JAD-180992.

    Article  PubMed  Google Scholar 

  11. Folch, J., Lees, M., & Sloane Stanley, G. H. (1957). A simple method for the isolation and purification of total lipides from animal tissues. Journal of Biological Chemistry, 226(1), 497–509.

    CAS  Article  Google Scholar 

  12. Gauthier, S., Feldman, H. H., Schneider, L. S., Wilcock, G. K., Frisoni, G. B., Hardlund, J. H., et al. (2016). Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: A randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet, 388(10062), 2873–2884. https://doi.org/10.1016/S0140-6736(16)31275-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Ginsberg, L., Rafique, S., Xuereb, J. H., Rapoport, S. I., & Gershfeld, N. L. (1995). Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer’s disease brain. Brain Research, 698(1–2), 223–226. https://doi.org/10.1016/0006-8993(95)00931-f.

    CAS  Article  PubMed  Google Scholar 

  14. Guan, Z., Wang, Y., Cairns, N. J., Lantos, P. L., Dallner, G., & Sindelar, P. J. (1999). Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 58(7), 740–747. https://doi.org/10.1097/00005072-199907000-00008.

    CAS  Article  PubMed  Google Scholar 

  15. Han, X., Holtzman, D. M., & McKeel, D. W., Jr. (2001). Plasmalogen deficiency in early Alzheimer’s disease subjects and in animal models: Molecular characterization using electrospray ionization mass spectrometry. Journal of Neurochemistry, 77(4), 1168–1180. https://doi.org/10.1046/j.1471-4159.2001.00332.x.

    CAS  Article  PubMed  Google Scholar 

  16. Heymans, H. S., Schutgens, R. B., Tan, R., van den Bosch, H., & Borst, P. (1983). Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome). Nature, 306(5938), 69–70. https://doi.org/10.1038/306069a0.

    CAS  Article  PubMed  Google Scholar 

  17. Hinton, L., Carter, K., Reed, B. R., Beckett, L., Lara, E., DeCarli, C., et al. (2010). Recruitment of a community-based cohort for research on diversity and risk of dementia. Alzheimer Disease and Associated Disorders, 24(3), 234–241. https://doi.org/10.1097/WAD.0b013e3181c1ee01.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., et al. (2012). National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement, 8(1), 1–13. https://doi.org/10.1016/j.jalz.2011.10.007.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Igarashi, M., Ma, K., Gao, F., Kim, H. W., Rapoport, S. I., & Rao, J. S. (2011). Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer’s disease prefrontal cortex [Research Support, N.I.H., Extramural Research]. Journal of Alzheimer’s Disease, 24(3), 507–517. https://doi.org/10.3233/jad-2011-101608.

    CAS  Article  PubMed  Google Scholar 

  20. Jellinger, K. A., & Attems, J. (2007). Neurofibrillary tangle-predominant dementia: Comparison with classical Alzheimer disease. Acta Neuropathologica, 113(2), 107–117. https://doi.org/10.1007/s00401-006-0156-7.

    CAS  Article  PubMed  Google Scholar 

  21. Kleineidam, L., Chouraki, V., Prochnicki, T., van der Lee, S. J., Madrid-Marquez, L., Wagner-Thelen, H., et al. (2020). PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. Acta Neuropathologica, 139(6), 1025–1044. https://doi.org/10.1007/s00401-020-02138-6.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kling, M. A., Goodenowe, D. B., Senanayake, V., MahmoudianDehkordi, S., Arnold, M., Massaro, T. J., et al. (2020). Circulating ethanolamine plasmalogen indices in Alzheimer’s disease: Relation to diagnosis, cognition, and CSF tau. Alzheimers Dement. https://doi.org/10.1002/alz.12110.

    Article  PubMed  Google Scholar 

  23. Lukiw, W. J., Cui, J. G., Marcheselli, V. L., Bodker, M., Botkjaer, A., Gotlinger, K., et al. (2005). A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. The Journal of Clinical Investigation, 115(10), 2774–2783. https://doi.org/10.1172/JCI25420.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Marinetti, G. V., & Erbland, J. (1957). The structure of pig heart plasmalogen. Biochimica et Biophysica Acta, 26(2), 429–430. https://doi.org/10.1016/0006-3002(57)90028-8.

    CAS  Article  PubMed  Google Scholar 

  25. McKeith, I. G., Dickson, D. W., Lowe, J., Emre, M., O’Brien, J. T., Feldman, H., et al. (2005). Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology, 65(12), 1863–1872. https://doi.org/10.1212/01.wnl.0000187889.17253.b1.

    CAS  Article  PubMed  Google Scholar 

  26. Montine, T. J., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Dickson, D. W., et al. (2012). National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: A practical approach. Acta Neuropathologica, 123(1), 1–11. https://doi.org/10.1007/s00401-011-0910-3.

    CAS  Article  PubMed  Google Scholar 

  27. O’Brien, J. S., & Sampson, E. L. (1965). Lipid composition of the normal human brain: Gray matter, white matter, and myelin. Journal of Lipid Research, 6(4), 537–544.

    Article  Google Scholar 

  28. Ostrowitzki, S., Lasser, R. A., Dorflinger, E., Scheltens, P., Barkhof, F., Nikolcheva, T., et al. (2017). A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Research & Therapy. https://doi.org/10.1186/s13195-017-0318-y.

    Article  Google Scholar 

  29. Otoki, Y., Hennebelle, M., Levitt, A. J., Nakagawa, K., Swardfager, W., & Taha, A. Y. (2017a). Plasma phosphatidylethanolamine and triacylglycerol fatty acid concentrations are altered in major depressive disorder patients with seasonal pattern. Lipids, 52(6), 559–571. https://doi.org/10.1007/s11745-017-4254-1.

    CAS  Article  PubMed  Google Scholar 

  30. Otoki, Y., Kato, S., Kimura, F., Furukawa, K., Yamashita, S., Arai, H., et al. (2017b). Accurate quantitation of choline and ethanolamine plasmalogen molecular species in human plasma by liquid chromatography-tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 134, 77–85. https://doi.org/10.1016/j.jpba.2016.11.019.

    CAS  Article  PubMed  Google Scholar 

  31. Panganamala, R. V., Horrocks, L. A., Geer, J. C., & Cornwell, D. G. (1971). Positions of double bonds in the monounsaturated alk-1-enyl groups from the plasmalogens of human heart and brain. Chemistry and Physics of Lipids, 6(2), 97–102. https://doi.org/10.1016/0009-3084(71)90031-4.

    CAS  Article  PubMed  Google Scholar 

  32. Pettegrew, J. W., Panchalingam, K., Hamilton, R. L., & McClure, R. J. (2001). Brain membrane phospholipid alterations in Alzheimer’s disease. Neurochemical Research, 26(7), 771–782. https://doi.org/10.1023/a:1011603916962.

    CAS  Article  PubMed  Google Scholar 

  33. Rosenberger, T. A., Oki, J., Purdon, A. D., Rapoport, S. I., & Murphy, E. J. (2002). Rapid synthesis and turnover of brain microsomal ether phospholipids in the adult rat. Journal of Lipid Research, 43(1), 59–68.

    CAS  Article  Google Scholar 

  34. Rothhaar, T. L., Grosgen, S., Haupenthal, V. J., Burg, V. K., Hundsdorfer, B., Mett, J., et al. (2012). Plasmalogens inhibit APP processing by directly affecting gamma-secretase activity in Alzheimer’s disease. The Scientific World Journal, 2012, 141240. https://doi.org/10.1100/2012/141240.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Sanchez-Mejia, R. O., Newman, J. W., Toh, S., Yu, G. Q., Zhou, Y., Halabisky, B., et al. (2008). Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer’s disease. Nature Neuroscience, 11(11), 1311–1318. https://doi.org/10.1038/nn.2213.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Scheff, S. W., DeKosky, S. T., & Price, D. A. (1990). Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiology of Aging, 11(1), 29–37. https://doi.org/10.1016/0197-4580(90)90059-9.

    CAS  Article  PubMed  Google Scholar 

  37. Senyilmaz-Tiebe, D., Pfaff, D. H., Virtue, S., Schwarz, K. V., Fleming, T., Altamura, S., et al. (2018). Dietary stearic acid regulates mitochondria in vivo in humans. Nature Communications, 9(1), 3129. https://doi.org/10.1038/s41467-018-05614-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Strokin, M., Sergeeva, M., & Reiser, G. (2003). Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. British Journal of Pharmacology, 139(5), 1014–1022. https://doi.org/10.1038/sj.bjp.0705326.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Suckau, O., Gross, I., Schrotter, S., Yang, F., Luo, J., Wree, A., et al. (2019). LPA1, LPA2, LPA4, and LPA6 receptor expression during mouse brain development. Developmental Dynamics, 248(5), 375–395. https://doi.org/10.1002/dvdy.23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Taha, A. Y., Cheon, Y., Ma, K., Rapoport, S. I., & Rao, J. S. (2013). Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients. Journal of Psychiatric Research, 47(5), 636–643. https://doi.org/10.1016/j.jpsychires.2013.01.016.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang, X., Zhu, M., Hjorth, E., Cortes-Toro, V., Eyjolfsdottir, H., Graff, C., et al. (2015). Resolution of inflammation is altered in Alzheimer’s disease. Alzheimers Dement. https://doi.org/10.1016/j.jalz.2013.12.024.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wood, P. L., Barnette, B. L., Kaye, J. A., Quinn, J. F., & Woltjer, R. L. (2015). Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer’s disease subjects. Acta Neuropsychiatrica, 27(5), 270–278. https://doi.org/10.1017/neu.2015.18.

    Article  PubMed  Google Scholar 

  43. Wood, P. L., Mankidy, R., Ritchie, S., Heath, D., Wood, J. A., Flax, J., et al. (2010). Circulating plasmalogen levels and Alzheimer Disease Assessment Scale-Cognitive scores in Alzheimer patients. Journal of Psychiatry and Neuroscience, 35(1), 59–62. https://doi.org/10.1503/jpn.090059.

    Article  PubMed  Google Scholar 

  44. Yamamuro, Y., Yamaguchi, Y., Abe, S., & Takenaga, F. (2013). Neurochemical and behavioural impact of C18 fatty acids in male mice postweaning. Experimental Biology and Medicine, 238(6), 658–667. https://doi.org/10.1177/1535370213489451.

    CAS  Article  PubMed  Google Scholar 

  45. Zhu, M., Wang, X., Hjorth, E., Colas, R. A., Schroeder, L., Granholm, A. C., et al. (2016). Pro-resolving lipid mediators improve neuronal survival and increase Abeta42 phagocytosis. Molecular Neurobiology, 53(4), 2733–2749. https://doi.org/10.1007/s12035-015-9544-0.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank the families and participants of the UCD ADRC for their generous donations. Research reported in this publication was supported by the National Institute On Aging of the National Institutes of Health under Award Number P30AG010129, Alzheimer’s Association (2018-AARGD-591676) and by the Project of the NARO Bio-oriented Technology Research Advancement Institution (R&D matching funds on the field for Knowledge Integration and innovation) under Award number 1074345. Y.O. is a recipient of a fellowship from the Japan Society for the Promotion of Science Core-to-Core Program, A (Advanced Research Networks entitled “Establishment of international agricultural immunology research-core for a quantum improvement in food safety”). The authors would like to thank Dr. Shinichi Sakasegawa and Mr. Kenji Konishi in Asahi Kasei Pharma Corporation for providing phospholipase A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding agencies involved.

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Study design—all authors, Experimental work—Y.O., S.K., Data analysis— Y.O., A.T., D.H., B.D L.J, Writing manuscript—Y.O., A.T., Funding acquisition, A.T. and K.N.

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Correspondence to Ameer Y. Taha.

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The study was approved by the Institutional Review Board of the University of California Davis, and written consent was obtained for each participant for autopsy evaluations (Protocol # 215830).

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Otoki, Y., Kato, S., Nakagawa, K. et al. Lipidomic Analysis of Postmortem Prefrontal Cortex Phospholipids Reveals Changes in Choline Plasmalogen Containing Docosahexaenoic Acid and Stearic Acid Between Cases With and Without Alzheimer’s Disease. Neuromol Med (2021). https://doi.org/10.1007/s12017-020-08636-w

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Keywords

  • Plasmalogens
  • Lipids
  • Alkyl-acyl phospholipids
  • Lysophospholipids
  • Alzheimer’s disease
  • Prefrontal cortex