Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally
Abstract
The synthesis of brain phosphatidylcholine may utilize three circulating precursors: choline; a pyrimidine (e.g., uridine, converted via UTP to brain CTP); and a PUFA (e.g., docosahexaenoic acid); phosphatidylethanolamine may utilize two of these, a pyrimidine and a PUFA. We observe that consuming these precursors can substantially increase membrane phosphatide and synaptic protein levels in gerbil brains. (Pyrimidine metabolism in gerbils, but not rats, resembles that in humans.) Animals received, daily for 4 weeks, a diet containing choline chloride and UMP (a uridine source) and/or DHA by gavage. Brain phosphatidylcholine rose by 13-22% with uridine and choline alone, or DHA alone, or by 45% with the combination, phosphatidylethanolamine and the other phosphatides increasing by 39-74%. Smaller elevations occurred after 1-3 weeks. The combination also increased the vesicular protein Synapsin-1 by 41%, the postsynaptic protein PSD-95 by 38% and the neurite neurofibrillar proteins NF-70 and NF-M by up to 102% and 48%, respectively. However, it had no effect on the cytoskeletal protein beta-tubulin. Hence, the quantity of synaptic membrane probably increased. The precursors act by enhancing the substrate saturation of enzymes that initiate their incorporation into phosphatidylcholine and phosphatidylethanolamine and by UTP-mediated activation of P2Y receptors. Alzheimer's disease brains contain fewer and smaller synapses and reduced levels of synaptic proteins, membrane phosphatides, choline and DHA. The three phosphatide precursors might thus be useful in treating this disease.
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Co-administration of uridine, docosahexaenoic acid, and choline can increase the amount of phospholipids, synaptic proteins, dendritic spine density and neurite outgrowth in rodents.
“Several studies in rodents showed that co-administration of uridine, DHA, and choline can increase the amount of phospholipids, synaptic proteins, dendritic spine density and neurite outgrowth (Holguin et al., 2008;Sakamoto et al., 2007;Wurtman et al., 2006).”
From The Gut-Brain Axis in Parkinson’s Disease: Possibilities for Food-Based Therapies (2017) · cites this paper as Wurtman et al., 2006
Cites
A SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
Folch, J., Lees, M., & Stanley, G. H. S. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64849-5 · Cited by 65,189 · see citing works
A simple, rapid, and sensitive DNA assay procedure
Labarca, C. G., & Paigen, K. (1980) · Analytical Biochemistry · doi:10.1016/0003-2697(80)90165-7 · Cited by 4,865 · see citing works
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420 · see citing works
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397 · see citing works
THE FUNCTION OF CYTIDINE COENZYMES IN THE BIOSYNTHESIS OF PHOSPHOLIPIDES
Kennedy, E. P., & Weiss, S. B. (1956) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)50785-2 · Cited by 1,825 · see citing works
Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease
Söderberg, M., Edlund, C., Kristensson, K., & Dallner, G. (1991) · Lipids · doi:10.1007/bf02536067 · Cited by 667 · see citing works
Evidence for a membrane defect in Alzheimer disease brain.
Nitsch, R. M., Blusztajn, J. K., Pittas, A. G., Slack, B. E., Growdon, J. H., & Wurtman, R. J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.5.1671 · Cited by 536 · see citing works
Self-citationMcCann, J. C., & Ames, B. N. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn.82.2.281 · Cited by 498 · see citing works
McCann, J. C., & Ames, B. N. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/82.2.281 · Cited by 412 · see citing works
Brain Acetylcholine: Control by Dietary Choline
Cohen, E. L., & Wurtman, R. J. (1976) · Science · doi:10.1126/science.1251187 · Cited by 390 · see citing works
Self-citationEncyclopedia of Dietary Supplements
(2010) · CRC Press eBooks · doi:10.1201/b14669 · Cited by 380 · see citing works
Hashimoto, M., Hossain, S., Shimada, T., Sugioka, K., Yamasaki, H., Fujii, Y., Ishibashi, Y., Oka, J., & Shido, O. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00905.x · Cited by 364 · see citing works
Svanborg, A., Svennerholm, L. T., Myrén, I., Soomägi, M. R., CLAESSON, B. O., & Rohman, S. (1961) · Acta Medica Scandinavica · doi:10.1111/j.0954-6820.1961.tb17091.x · Cited by 326 · see citing works
A focus on the synapse for neuroprotection in Alzheimer disease and other dementias
Coleman, P., Federoff, H., & Kurlan, R. (2004) · Neurology · doi:10.1212/01.wnl.0000140626.48118.0a · Cited by 314 · see citing works
Marszalek, J. R., & Lodish, H. F. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.122303.120624 · Cited by 270 · see citing works
Encyclopedia of dietary supplements
(2005) · Choice Reviews Online · doi:10.5860/choice.43-0034 · Cited by 249 · see citing works
CARRIER MEDIATED BLOOD‐BRAIN BARRIER TRANSPORT OF CHOLINE AND CERTAIN CHOLINE ANALOGS
Cornford, E. M., Braun, L. D., & Oldendorf, W. H. (1978) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1978.tb06530.x · Cited by 220 · see citing works
Rapoport, S. I. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:16:2-3:243 · Cited by 215 · see citing works
Plasma Free Fatty Acid and Lipoproteins as Sources of Polyunsaturated Fatty Acid for the Brain
Spector, A. A. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:16:2-3:159 · Cited by 189 · see citing works
Ulus, İ. H., Wurtman, R. J., Mauron, C., & Blusztajn, J. K. (1989) · Brain Research · doi:10.1016/0006-8993(89)90364-8 · Cited by 182 · see citing works
Self-citationThe synapsins: beyond the regulation of neurotransmitter release
Ferreira, A., & Rapoport, M. I. (2002) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-002-8451-5 · Cited by 153 · see citing works
Effect of oral CDP-choline on plasma choline and uridine levels in humans
Wurtman, R. J., Regan, M. M., Ulus, İ. H., & Yu, L. (2000) · Biochemical Pharmacology · doi:10.1016/s0006-2952(00)00436-6 · Cited by 145 · see citing works
Self-citationLong-chain Acyl-CoA Synthetase 6 Preferentially Promotes DHA Metabolism
Marszalek, J. R., Kitidis, C., Dirusso, C., & Lodish, H. F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411750200 · Cited by 130 · see citing works
Uridine enhances neurite outgrowth in nerve growth factor-differentiated pheochromocytoma cells
Pooler, A. M., Guez, D. H., Benedictus, R., & Wurtman, R. J. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.03.050 · Cited by 110 · see citing works
Self-citationThe metabolism of [Me−14C]choline in the brain of the rat in vivo
ANSELL, G. B., & Spanner, S. (1968) · Biochemical Journal · doi:10.1042/bj1100201 · Cited by 109 · see citing works
Stalenhoef, A. F. H., Graaf, J. D., Wittekoek, M. E., Bredie, S. J. H., Demacker, P. N. M., & Kastelein, J. J. P. (2000) · Atherosclerosis · doi:10.1016/s0021-9150(00)00381-6 · Cited by 101 · see citing works
López-Coviella, I., Agut, J., Savcı, V., et al. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65020889.x · Cited by 99 · see citing works
Fujita, A., & Kurachi, Y. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1893 · Cited by 89 · see citing works
Choline Administration Elevates Brain Phosphorylcholine Concentrations
Millington, W. R., & Wurtman, R. J. (1982) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1982.tb06658.x · Cited by 89 · see citing works
Self-citationAraki, W., & Wurtman, R. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.22.11946 · Cited by 87 · see citing works
Self-citationScientific rationale and benefits of nucleotide supplementation of infant formula*
Yu, V. (2002) · Journal of Paediatrics and Child Health · doi:10.1046/j.1440-1754.2002.00056.x · Cited by 83 · see citing works
Induction of neurofilament triplet proteins in PC12 cells by nerve growth factor
Lee, V., Trojanowski, J. Q., & Schlaepfer, W. W. (1982) · Brain Research · doi:10.1016/0006-8993(82)90779-x · Cited by 82 · see citing works
Structural Basis for the Specificity, Catalysis, and Regulation of Human Uridine-Cytidine Kinase
Suzuki, N. N., Koizumi, K., Fukushima, M., et al. (2004) · Structure · doi:10.1016/j.str.2004.02.038 · Cited by 82 · see citing works
Li, J. Y., Boado, R. J., & Pardridge, W. M. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200108000-00005 · Cited by 80 · see citing works
Oral uridine-5′-monophosphate (UMP) increases brain CDP-choline levels in gerbils
Cansev, M., Watkins, C. J., van der Beek, E. M., & Wurtman, R. J. (2005) · Brain Research · doi:10.1016/j.brainres.2005.07.054 · Cited by 65 · see citing works
Self-citationPhospholipid biosynthetic enzymes in human brain
Ross, B. M., Moszczyńska, A., Blusztajn, J. K., Sherwin, A. L., Lozano, A. M., & Kish, S. J. (1997) · Lipids · doi:10.1007/s11745-997-0044-x · Cited by 64 · see citing works
Wang, L., Pooler, A. M., Albrecht, M. A., & Wurtman, R. J. (2005) · Journal of Molecular Neuroscience · doi:10.1385/jmn:27:1:137 · Cited by 57 · see citing works
Self-citationStimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cells
Richardson, U. I., Watkins, C. J., Pierre, C., et al. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02333-3 · Cited by 57 · see citing works
Self-citationOral choline increases choline metabolites in human brain
Babb, S. M., Ke, Y., LANGE, N. D., Kaufman, M. J., Renshaw, P. F., & Cohen, B. M. (2003) · Psychiatry Research Neuroimaging · doi:10.1016/s0925-4927(03)00104-5 · Cited by 54 · see citing works
Choline kinase and ethanolamine kinase activity in the cytosol of nerve endings from rat forebrain
Spanner, S., & ANSELL, G. B. (1979) · Biochemical Journal · doi:10.1042/bj1780753 · Cited by 47 · see citing works
Teather, L. A., & Wurtman, R. J. (2003) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(03)00086-1 · Cited by 44 · see citing works
Self-citationTeather, L. A., & Wurtman, R. J. (2005) · Learning & Memory · doi:10.1101/lm.83905 · Cited by 41 · see citing works
Self-citationEnhancement of free fatty acid incorporation into phospholipids by choline plus cytidine
Knapp, S., & Wurtman, R. J. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01072-0 · Cited by 21 · see citing works
Self-citationCTP SYNTHETASE ACTIVITY IN NEONATAL AND ADULT RAT BRAIN
Genchev, D. D., & Mandel, P. (1974) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1974.tb04332.x · Cited by 19 · see citing works
Harris, R. P. (2006) · Cited by 17 · see citing works
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Soininen, H., Solomon, A., Visser, P. J., Hendrix, S. B., Blennow, K., Kivipelto, M., Hartmann, T., Hallikainen, I., Hallikainen, M., Helisalmi, S., et al. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30332-0 · Cited by 241 · see citing works
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Perez-Pardo, P., Kliest, T., Dodiya, H. B., Broersen, L. M., Garssen, J., Keshavarzian, A., & Kraneveld, A. D. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.05.042 · Cited by 203 · see citing works
Sakamoto, T., Cansev, M., & Wurtman, R. J. (2007) · Brain Research · doi:10.1016/j.brainres.2007.08.089 · Cited by 188 · see citing works
Self-citationvan Wijk, N., Broersen, L. M., de Wilde, M. C., Hageman, R. J. J., Groenendijk, M., Sijben, J. W. C., & Kamphuis, P. J. G. H. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130998 · Cited by 128 · see citing works
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Cansev, M., Ulus, I. H., Wang, L., Maher, T. J., & Wurtman, R. J. (2008) · Neuroscience Research · doi:10.1016/j.neures.2008.07.005 · Cited by 81 · see citing works
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Wurtman, R. (2014) · Nutrients · doi:10.3390/nu6041701 · Cited by 68 · see citing works
Self-citationOlde Rikkert, M. G. M., Verhey, F. R., Blesa, R., von Arnim, C. A. F., Bongers, A., Harrison, J., Sijben, J., Scarpini, E., Vandewoude, M. F. J., Vellas, B., et al. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-141305 · Cited by 61 · see citing works
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Wiesmann, M., Zerbi, V., Jansen, D., Haast, R., Lütjohann, D., Broersen, L. M., Heerschap, A., & Kiliaan, A. J. (2016) · Neural Plasticity · doi:10.1155/2016/6846721 · Cited by 60 · see citing works
Holguin, S., Huang, Y., Liu, J., & Wurtman, R. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.02.042 · Cited by 57 · see citing works
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- Authors
- Wurtman, R. J., Ulus, I. H., Cansev, M., Watkins, C. J., Wang, L., & Marzloff, G.
- Affiliations
- Massachusetts Institute of Technology (US)
- Bursa Uludağ Üni̇versi̇tesi̇ (TR)
- Corresponding author
- Wurtman, Richard J.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 1088
- Issue
- 1
- Pages
- 83-92
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W1978524806
- Cited by
- 169
- References
- 45
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 4 · 2018: 8 · 2017: 12 · 2016: 9 · 2015: 14 · 2014: 12 · 2013: 17 · 2012: 6
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Bursa Uludag University - AVESIS (submittedVersion)
- Funders
- Türkiye Bilimler Akademisi
- National Institutes of Health
- U.S. Food and Drug Administration
- National Institute of Mental Health (MH 28783)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- uridine, docosahexaenoic acid, choline, phosphatidylcholine synthesis, phosphatidylethanolamine, synaptic proteins, synapsin-1, PSD-95, neurofibrillary tangles, brain phospholipids, P2Y receptors, UTP, Alzheimer's disease, gerbil brain, dietary precursors
- MeSH terms
- Administration, Oral, Animals, Brain, Choline, Diet, Docosahexaenoic Acids, Gerbillinae, Male, Nerve Tissue Proteins, Phospholipids, Synapses, Time Factors, Uridine, Gene Expression, Synapsins
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