Skip to main content

Advertisement

SpringerLink
Log in

Cerebrospinal fluid lipidomics: effects of an intravenous triglyceride infusion and apoE status

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Introduction

High-fat diets increase risk for Alzheimer’s disease, but individuals with the risk gene APOE ε4 (E4) paradoxically have improved memory soon after high fat feeding. Little is known about how dietary lipids affect CNS lipids, especially in older adults.

Objectives

We analyzed the lipidomic signature of cerebrospinal fluid (CSF) in older adults who underwent both a saline and TG infusion. We further analyzed these data by E4 carrier status.

Methods

Older adults (n = 21, age 67.7 ± 8.6) underwent a 5-h TG and saline infusion on different days in random crossover design; lumbar CSF was collected at the end of the infusion. Lipids were extracted using dichloromethane/methanol and 13 classes of lipids analyzed using the Lipidyzer platform consisting of an AB Sciex 5500 MS/MS QTraps system equipped with a SelexION for differential mobility spectrometry (DMS). Multiple reaction monitoring was used to target and quantify 1070 lipids in positive and negative ionization modes with and without DMS.

Results

The TG infusion increased total lipids in the CSF, including the appearance of more lipids at the detection limit in the TG samples compared to saline (Chi square p < 0.0001). The infusion increased the total level of diacylglycerols and lysophosphatidylcholines and reduced dihydroceramides. Of the possible 1070 lipids detectable, we found 348 after saline and 365 after TG infusion. Analysis using MetaboAnalyst revealed 11 specific lipids that changed; five of these lipids decreased after TG infusion, and four of them differed by E4 status, but none differed by cognitive diagnosis or sex.

Conclusion

These results in older adults show that blood lipids affect lipid profiles in CSF and such profiles are modified by APOE status. This suggests that how the CNS handles lipids may be important in the AD phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Alberghina, M., Lupo, G., Anfuso, C. D., & Moro, F. (1993). Palmitate transport through the blood-retina and blood-brain barrier of rat visual system during aging. Neuroscience Letters, 150, 17–20.

    CAS  PubMed  Google Scholar 

  • Arai, T., Wakabayashi, S., Channing, M. A., Dunn, B. B., Der, M. G., Bell, J. M., et al. (1995). Incorporation of [1-carbon-11]palmitate in monkey brain using PET. Journal of Nuclear Medicine, 36, 2261–2267.

    CAS  PubMed  Google Scholar 

  • Astarita, G., Jung, K. M., Vasilevko, V., Dipatrizio, N. V., Martin, S. K., Cribbs, D. H., et al. (2011). Elevated stearoyl-CoA desaturase in brains of patients with Alzheimer’s disease. PLoS ONE, 6, e24777.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bandaru, V. V., Mielke, M. M., Sacktor, N., McArthur, J. C., Grant, I., Letendre, S., et al. (2013). A lipid storage-like disorder contributes to cognitive decline in HIV-infected subjects. Neurology, 81, 1492–1499.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Banks, W. A., Farr, S. A., Salameh, T. S., Niehoff, M. L., Rhea, E. M., Morley, J. E., et al. (2017). Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance. International Journal of Obesity (London), 42(3), 391–397.

    Google Scholar 

  • Barberger-Gateau, P., Samieri, C., Feart, C., & Plourde, M. (2011). Dietary omega 3 polyunsaturated fatty acids and Alzheimer’s disease: interaction with apolipoprotein E genotype. Current Alzheimer Research, 8, 479–491.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barnes, D. E., & Yaffe, K. (2011). The projected effect of risk factor reduction on Alzheimer’s disease prevalence. The Lancet Neurology, 10, 819–828.

    PubMed  PubMed Central  Google Scholar 

  • Blasco, H., Veyrat-Durebex, C., Bocca, C., Patin, F., Vourc’h, P., Kouassi Nzoughet, J., et al. (2017). Lipidomics reveals cerebrospinal-fluid signatures of ALS. Scientific Reports, 7, 17652.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Braverman, N. E., & Moser, A. B. (2012). Functions of plasmalogen lipids in health and disease. Biochimica et Biophysica Acta, 1822, 1442–1452.

    CAS  PubMed  Google Scholar 

  • Chen, C. T., Green, J. T., Orr, S. K., & Bazinet, R. P. (2008). Regulation of brain polyunsaturated fatty acid uptake and turnover. Prostaglandins Leukotrienes and Essential Fatty Acids, 79, 85–91.

    CAS  Google Scholar 

  • Dallongeville, J., Lussier-Cacan, S., & Davignon, J. (1992). Modulation of plasma triglyceride levels by apoE phenotype: A meta-analysis. Journal of Lipid Research, 33, 447–454.

    CAS  PubMed  Google Scholar 

  • Ebert, D., Haller, R. G., & Walton, M. E. (2003). Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. Journal of Neuroscience, 23, 5928–5935.

    CAS  PubMed  Google Scholar 

  • Edmond, J. (2001). Essential polyunsaturated fatty acids and the barrier to the brain: The components of a model for transport. Journal of Molecular Neuroscience, 16, 181–193.

    CAS  PubMed  Google Scholar 

  • Emmerich, T., Abdullah, L., Crynen, G., Dretsch, M., Evans, J., Ait-Ghezala, G., et al. (2016). Plasma lipidomic profiling in a military population of mild traumatic brain injury and post-traumatic stress disorder with apolipoprotein E varepsilon4-Dependent Effect. Journal of Neurotrauma, 33, 1331–1348.

    PubMed  Google Scholar 

  • Fan, J., Donkin, J., & Wellington, C. (2009). Greasing the wheels of Abeta clearance in Alzheimer’s disease: The role of lipids and apolipoprotein E. BioFactors, 35, 239–248.

    CAS  PubMed  Google Scholar 

  • Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., et al. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA, 278, 1349–1356.

    CAS  PubMed  Google Scholar 

  • Fonteh, A. N., Chiang, J., Cipolla, M., Hale, J., Diallo, F., Chirino, A., et al. (2013). Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. Journal of Lipid Research, 54, 2884–2897.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fonteh, A. N., Cipolla, M., Chiang, J., Arakaki, X., & Harrington, M. G. (2014). Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease. PLoS ONE, 9, e100519.

    PubMed  PubMed Central  Google Scholar 

  • Frisardi, V., Panza, F., Seripa, D., Farooqui, T., & Farooqui, A. A. (2011). Glycerophospholipids and glycerophospholipid-derived lipid mediators: A complex meshwork in Alzheimer’s disease pathology. Progress in Lipid Research, 50, 313–330.

    CAS  PubMed  Google Scholar 

  • Garcia del Cano, G., Montana, M., Aretxabala, X., Gonzalez-Burguera, I., Lopez de Jesus, M., Barrondo, S., et al. (2014). Nuclear phospholipase C-beta1 and diacylglycerol LIPASE-alpha in brain cortical neurons. Advances Biological Regulation, 54, 12–23.

    CAS  Google Scholar 

  • Gardener, S., Gu, Y., Rainey-Smith, S. R., Keogh, J. B., Clifton, P. M., Mathieson, S. L., et al. (2012). Adherence to a Mediterranean diet and Alzheimer’s disease risk in an Australian population. Translational Psychiatry, 2, e164.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grimm, M. O. W., Michaelson, D. M., & Hartmann, T. (2017). Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer’s disease: A rationale for multi-nutrient dementia prevention. Journal of Lipid Research, 58, 2083–2101.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gustaw-Rothenberg, K. (2009). Dietary patterns associated with Alzheimer’s disease: Population based study. International Journal of Environmental Research and Public Health, 6, 1335–1340.

    PubMed  PubMed Central  Google Scholar 

  • Hamilton, J. A., & Brunaldi, K. (2007). A model for fatty acid transport into the brain. Journal of Molecular Neuroscience, 33, 12–17.

    CAS  PubMed  Google Scholar 

  • Hanson, A. J., Bayer, J. L., Baker, L. D., Cholerton, B., VanFossen, B., Trittschuh, E., et al. (2015). Differential effects of meal challenges on cognition, metabolism, and biomarkers for apolipoprotein E varepsilon4 carriers and adults with mild cognitive impairment. Journal of Alzheimer’s Disease, 48, 205–218.

    CAS  PubMed  Google Scholar 

  • Hanson, A. J., Bayer-Carter, J. L., Green, P. S., Montine, T. J., Wilkinson, C. W., Baker, L. D., et al. (2013). Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: Randomized clinical trial. JAMA Neurology, 70(8), 1–9.

    Google Scholar 

  • Haughey, N. J., Zhu, X., & Bandaru, V. V. (2013). A biological perspective of CSF lipids as surrogate markers for cognitive status in HIV. Journal of Neuroimmune Pharmacology, 8, 1136–1146.

    PubMed  PubMed Central  Google Scholar 

  • Hixson, J. E., & Vernier, D. T. (1990). Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. Journal of Lipid Research, 31, 545–548.

    CAS  PubMed  Google Scholar 

  • Huang, T. L., Zandi, P. P., Tucker, K. L., Fitzpatrick, A. L., Kuller, L. H., Fried, L. P., et al. (2005). Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology, 65, 1409–1414.

    CAS  PubMed  Google Scholar 

  • Johnson, L. A., Torres, E. R., Impey, S., Stevens, J. F., & Raber, J. (2017). Apolipoprotein E4 and insulin resistance interact to impair cognition and alter the epigenome and metabolome. Scientific Reports, 7, 43701.

    PubMed  PubMed Central  Google Scholar 

  • Jumpertz, R., Guijarro, A., Pratley, R. E., Mason, C. C., Piomelli, D., & Krakoff, J. (2012). Associations of fatty acids in cerebrospinal fluid with peripheral glucose concentrations and energy metabolism. PLoS ONE, 7, e41503.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kasser, T. R., Deutch, A., & Martin, R. J. (1986). Uptake and utilization of metabolites in specific brain sites relative to feeding status. Physiology & Behavior, 36, 1161–1165.

    CAS  Google Scholar 

  • Kivipelto, M., Rovio, S., Ngandu, T., Kareholt, I., Eskelinen, M., Winblad, B., et al. (2008). Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: A population-based study. Journal of Cellular and Molecular Medicine, 12, 2762–2771.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kosicek, M., Zetterberg, H., Andreasen, N., Peter-Katalinic, J., & Hecimovic, S. (2012). Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer’s disease. Neuroscience Letters, 516, 302–305.

    CAS  PubMed  Google Scholar 

  • Lam, S. M., Wang, Y., Duan, X., Wenk, M. R., Kalaria, R. N., Chen, C. P., et al. (2014). Brain lipidomes of subcortical ischemic vascular dementia and mixed dementia. Neurobiology of Aging, 35, 2369–2381.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Lapiscina, E. H., Clavero, P., Toledo, E., Estruch, R., Salas-Salvado, J., San Julian, B., et al. (2013). Mediterranean diet improves cognition: The PREDIMED-NAVARRA randomised trial. Journal of Neurology, Neurosurgery and Psychiatry, 84, 1318–1325.

    PubMed  Google Scholar 

  • Moulle, V. S., Cansell, C., Luquet, S., & Cruciani-Guglielmacci, C. (2012). The multiple roles of fatty acid handling proteins in brain. Frontiers Physiology, 3, 385.

    Google Scholar 

  • Mulder, C., Wahlund, L. O., Teerlink, T., Blomberg, M., Veerhuis, R., van Kamp, G. J., et al. (2003). Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer’s disease. Journal of Neural Transmission, 110, 949–955.

    CAS  PubMed  Google Scholar 

  • Nelson, R. H., Mundi, M. S., Vlazny, D. T., Smailovic, A., Muthusamy, K., Almandoz, J. P., et al. (2013). Kinetics of saturated, monounsaturated, and polyunsaturated fatty acids in humans. Diabetes, 62, 783–788.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nuriel, T., Angulo, S. L., Khan, U., Ashok, A., Chen, Q., Figueroa, H. Y., et al. (2017). Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology. Nature Communications, 8, 1464.

    PubMed  PubMed Central  Google Scholar 

  • Paglia, G., Stocchero, M., Cacciatore, S., Lai, S., Angel, P., Alam, M. T., et al. (2016). Unbiased metabolomic investigation of Alzheimer’s disease brain points to dysregulation of mitochondrial aspartate metabolism. Journal of Proteome Research, 15, 608–618.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Plourde, M., Vohl, M. C., Vandal, M., Couture, P., Lemieux, S., & Cunnane, S. C. (2009). Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-alpha L162V polymorphism in men. British Journal of Nutrition, 102, 1121–1124.

    CAS  PubMed  Google Scholar 

  • Quinn, J. F., Raman, R., Thomas, R. G., Yurko-Mauro, K., Nelson, E. B., Van Dyck, C., et al. (2010). Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: A randomized trial. JAMA, 304, 1903–1911.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sakane, F., Mizuno, S., Takahashi, D., & Sakai, H. (2018). Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways. Advances in Biological Regulation, 67, 101–108.

    CAS  PubMed  Google Scholar 

  • Seyer, A., Boudah, S., Broudin, S., Junot, C., & Colsch, B. (2016). Annotation of the human cerebrospinal fluid lipidome using high resolution mass spectrometry and a dedicated data processing workflow. Metabolomics, 12, 91.

    PubMed  PubMed Central  Google Scholar 

  • Solfrizzi, V., Panza, F., Frisardi, V., Seripa, D., Logroscino, G., Imbimbo, B. P., et al. (2011). Diet and Alzheimer’s disease risk factors or prevention: The current evidence. Expert Review of Neurotherapeutics, 11, 677–708.

    CAS  PubMed  Google Scholar 

  • Stranahan, A. M., Cutler, R. G., Button, C., Telljohann, R., & Mattson, M. P. (2011). Diet-induced elevations in serum cholesterol are associated with alterations in hippocampal lipid metabolism and increased oxidative stress. Journal of Neurochemistry, 118, 611–615.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thon, M., Hosoi, T., Chea, C., & Ozawa, K. (2017). Loss of stearoyl-CoA desaturase-1 activity induced leptin resistance in neuronal cells. Biological and Pharmaceutical Bulletin, 40, 1161–1164.

    CAS  PubMed  Google Scholar 

  • Touboul, D., & Gaudin, M. (2014). Lipidomics of Alzheimer’s disease. Bioanalysis, 6, 541–561.

    CAS  PubMed  Google Scholar 

  • Tsivgoulis, G., Judd, S., Letter, A. J., Alexandrov, A. V., Howard, G., Nahab, F., et al. (2013). Adherence to a Mediterranean diet and risk of incident cognitive impairment. Neurology, 80, 1684–1692.

    PubMed  PubMed Central  Google Scholar 

  • van der Kant, R., Langness, V. F., Herrera, C. M., Williams, D. A., Fong, L. K., Leestemaker, Y., et al. (2019). Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-beta in iPSC-derived Alzheimer’s Disease neurons. Cell Stem Cell, 24(363–375), e9.

    Google Scholar 

  • Vidaurre, O. G., Haines, J. D., Katz Sand, I., Adula, K. P., Huynh, J. L., McGraw, C. A., et al. (2014). Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics. Brain, 137, 2271–2286.

    PubMed  PubMed Central  Google Scholar 

  • Williams, W. M., Chang, M. C., Hayakawa, T., Grange, E., & Rapoport, S. I. (1997). In vivo incorporation from plasma of radiolabeled palmitate and arachidonate into rat brain microvessels. Microvascular Research, 53, 163–166.

    CAS  PubMed  Google Scholar 

  • Wishart, D. S., Feunang, Y. D., Marcu, A., Guo, A. C., Liang, K., Vazquez-Fresno, R., et al. (2018). HMDB 4.0: The human metabolome database for 2018. Nucleic Acids Research, 46, D608–D617.

    CAS  PubMed  Google Scholar 

  • Wood, P. L. (2012). Lipidomics of Alzheimer’s disease: Current status. Alzheimers Research Therapy, 4, 5.

    CAS  Google Scholar 

Download references

Acknowledgements

Alzheimer’s disease research center at University of Washington, and the Northwest Metabolomics Research Center.

Funding

This study was funded by 1K23AG047978-01A1 and 1S10OD021562-01 from the National Institutes of Health, the Veterans Affairs Medical Center, and the Chair of Medicine scholars award from the University of Washington School of Medicine.

Author information

Authors and Affiliations

  1. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA

    Angela J. Hanson & William A. Banks

  2. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA

    William A. Banks

  3. Department of Anesthesiology and Pain Medicine, Northwest Metabolomics Research Center, University of Washington, Seattle, WA, USA

    Lisa F. Bettcher, Robert Pepin & Daniel Raftery

  4. Wake Forest School of Medicine, Department of Internal Medicine, Winston-Salem, NC, USA

    Suzanne Craft

Authors
  1. Angela J. Hanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William A. Banks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa F. Bettcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Pepin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Raftery
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suzanne Craft
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AJH conceptualized the study, undertook statistical analysis and interpreted results and wrote/revised manuscript; WAB conceptualized the study, assisted with result interpretation and revised manuscript; LFP and RP collected data, assisted with result interpretation and revised manuscript. DR conceptualized the study, assisted with result interpretation and revised manuscript. SC collected data and was the PI of the parent clinical study, and revised manuscript.

Corresponding author

Correspondence to Angela J. Hanson.

Ethics declarations

Conflict of interest

All authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board of the University of Washington and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 15 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hanson, A.J., Banks, W.A., Bettcher, L.F. et al. Cerebrospinal fluid lipidomics: effects of an intravenous triglyceride infusion and apoE status. Metabolomics 16, 6 (2020). https://doi.org/10.1007/s11306-019-1627-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11306-019-1627-x

Keywords

Search

Navigation