Advertisement

BioNanoScience

, Volume 8, Issue 1, pp 473–480 | Cite as

Intravenous Transplantation of Human Umbilical Cord Blood Mononuclear Cells Overexpressing Nerve Growth Factor Improves Spatial Memory in APP/PS1 Transgenic Mice with a Model of Alzheimer’s Disease

  • M. A. Mukhamedyarov
  • A. V. Leushina
  • A. E. Tikhonova
  • E. O. Petukhova
  • E. E. Garanina
  • R. Ben Taleb
  • M. S. Kaligin
  • Y. O. Mukhamedshina
  • A. A. Rizvanov
  • A. L. Zefirov
  • R. R. Islamov
Article

Abstract

Alzheimer’s disease is a progressive incurable neurodegenerative disease manifested by dementia and other cognitive disorders. Gene-cell therapy is one of the most promising trends in the development of treatment for Alzheimer’s disease. The study was aimed to evaluate the therapeutic potential of intravenous transplantation of human umbilical cord blood mononuclear cells (UCBMCs) transduced with adenoviral vectors overexpressing nerve growth factor (NGF) for the treatment of Alzheimer’s disease in an APP/PS1 transgenic mice model. The transplantation of NGF-expressing UCBMCs was found to improve spatial memory and decrease anxiety in APP/PS1 mice. Grafted cells and their expression of NGF were detected in the cortex and hippocampus of transgenic mice in the period up to 90 days after transplantation. Thus, gene-cell therapy based on the use of NGF-overexpressing UCBMCs is a promising approach for the development of Alzheimer’s disease treatments.

Keywords

Alzheimer’s disease Nerve growth factor Stem cells Gene-cell therapy APP/PS1 transgenic mice Umbilical cord blood mononuclear cells 

Notes

Acknowledgements

The study was supported by the Scholarship of the President of the Russian Federation for young researchers and scientists (СП-255.2016.4), RFFR grant no. 17-04-02175А. Some aspects of methodology for the development of gene-cell approaches to the treatment of neurodegenerative disorders were implemented with the support by the RSF grant no. 14-15-00847-П. Kazan Federal University facilities were supported by the Russian Government Program of Competitive Growth. Albert A. Rizvanov was personally supported by the state assignment 20.5175.2017/6.7 of the Ministry of Education and Science of the Russian Federation (“Leading Scientist”).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., & Jones, E. (2011). Alzheimer’s disease. Lancet, 377(9770), 1019–1031.  https://doi.org/10.1016/S0140-6736(10)61349-9.CrossRefGoogle Scholar
  2. 2.
    Querfurth, H. W., & LaFerla, F. M. (2010). Alzheimer’s disease. The New England Journal of Medicine, 362(4), 329–344.  https://doi.org/10.1056/NEJMra0909142.CrossRefGoogle Scholar
  3. 3.
    Mukhamedyarov, M. A., & Zefirov, A. L. (2013). The influence of beta-amyloid peptide on the functions of excitable tissues: physiological and pathological aspects. Uspekhi Fiziologicheskikh Nauk, 44(1), 55–71.Google Scholar
  4. 4.
    Mukhamedyarov, M. A., Rizvanov, A. A., Safiullov, Z. Z., Izmailov, A. A., Sharifullina, G. A., Solovieva, V. V., Fedotova, V. Y., Salafutdinov, I. I., Cherenkova, E. E., Bashirov, F. V., Kaligin, M. S., Abdulkhakov, S. R., Shmarov, M. M., Logunov, D. Y., Naroditsky, B. S., Kiyasov, A. P., Zefirov, A. L., & Islamov, R. R. (2013). Analysis of the efficiency of gene-cell therapy in transgenic mice with amyotrophic lateral sclerosis phenotype. Bulletin of Experimental Biology and Medicine, 154(4), 558–561.CrossRefGoogle Scholar
  5. 5.
    Islamov, R. R., Rizvanov, A. A., Mukhamedyarov, M. A., Salafutdinov, I. I., Garanina, E. E., Fedotova, V. Y., Solovyeva, V. V., Mukhamedshina, Y. O., Safiullov, Z. Z., Izmailov, A. A., Guseva, D. S., Zefirov, A. L., Kiyasov, A. P., & Palotas, A. (2015). Symptomatic improvement, increased life-span and sustained cell homing in amyotrophic lateral sclerosis after transplantation of human umbilical cord blood cells genetically modified with adeno-viral vectors expressing a neuro-protective factor and a neural cell adhesion molecule. Current Gene Therapy, 15(3), 266–276.CrossRefGoogle Scholar
  6. 6.
    Islamov, R. R., Rizvanov, A. A., Fedotova, V. Y., Izmailov, A. A., Safiullov, Z. Z., Garanina, E. E., Salafutdinov, I. I., Sokolov, M. E., Mukhamedyarov, M. A., & Palotas, A. (2017). Tandem delivery of multiple therapeutic genes using umbilical cord blood cells improves symptomatic outcomes in ALS. Molecular Neurobiology, 54(6), 4756–4763.  https://doi.org/10.1007/s12035-016-0017-x.CrossRefGoogle Scholar
  7. 7.
    Tuszynski, M. H. (2007). Nerve growth factor gene therapy in Alzheimer disease. Alzheimer Disease and Associated Disorders, 21(2), 179–189.  https://doi.org/10.1097/WAD.0b013e318068d6d2.CrossRefGoogle Scholar
  8. 8.
    Petukhova, E. O., Mukhamedshina, Y. O., Rizvanov, A. A., Mukhitov, A. R., Zefirov, A. L., Islamov, R. R., & Mukhamedyarov, M. A. (2014). Transplantation of mononuclear cells of human umbilical cord blood improves spatial memory in APP/PS1 transgenic mice with Alzheimer’s disease model. Genes and Cells, 9(3), 234–239.Google Scholar
  9. 9.
    Misko, T. P., Radeke, M. J., & Shooter, E. M. (1987). Nerve growth factor in neuronal development and maintenance. The Journal of Experimental Biology, 132, 177–190.Google Scholar
  10. 10.
    Huang, E. J., & Reichardt, L. F. (2001). Neurotrophins: roles in neuronal development and function. Annual Review of Neuroscience, 24, 677–736.  https://doi.org/10.1146/annurev.neuro.24.1.677.CrossRefGoogle Scholar
  11. 11.
    Salehi, A., Delcroix, J. D., & Swaab, D. F. (2004). Alzheimer’s disease and NGF signaling. Journal of Neural Transmission, 111(3), 323–345.  https://doi.org/10.1007/s00702-003-0091-x.CrossRefGoogle Scholar
  12. 12.
    Lorigados, L., Alvarez, P., Pavon, N., Serrano, T., Blanco, L., & Macias, R. (1996). NGF in experimental models of Parkinson disease. Molecular and Chemical Neuropathology, 28(1–3), 225–228.  https://doi.org/10.1007/BF02815226.CrossRefGoogle Scholar
  13. 13.
    Galpern, W. R., Matthews, R. T., Beal, M. F., & Isacson, O. (1996). NGF attenuates 3-nitrotyrosine formation in a 3-NP model of Huntington’s disease. Neuroreport, 7(15–17), 2639–2642.CrossRefGoogle Scholar
  14. 14.
    Ekestern, E. (2004). Neurotrophic factors and amyotrophic lateral sclerosis. Neuro-Degenerative Diseases, 1(2–3), 88–100.  https://doi.org/10.1159/000080049.CrossRefGoogle Scholar
  15. 15.
    Hawley, T. S., Herbert, D. J., Eaker, S. S., & Hawley, R. G. (2004). Multiparameter flow cytometry of fluorescent protein reporters. Methods in Molecular Biology, 263, 219–238.  https://doi.org/10.1385/1-59259-773-4:219.Google Scholar
  16. 16.
    Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227(5259), 680–685.CrossRefGoogle Scholar
  17. 17.
    Deacon, R. M., & Rawlins, J. N. (2006). T-maze alternation in the rodent. Nature Protocols, 1(1), 7–12.  https://doi.org/10.1038/nprot.2006.2.CrossRefGoogle Scholar
  18. 18.
    Salimov, R. M., McBride, W. J., Sinclair, J. D., Lumeng, L., & Li, T. (1996). Performance in the cross-maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior. Addiction Biology, 1(3), 273–280.  https://doi.org/10.1080/1355621961000124886.CrossRefGoogle Scholar
  19. 19.
    Pezet, S., & McMahon, S. B. (2006). Neurotrophins: mediators and modulators of pain. Annual Review of Neuroscience, 29, 507–538.  https://doi.org/10.1146/annurev.neuro.29.051605.112929.CrossRefGoogle Scholar
  20. 20.
    Cirulli, F., Alleva, E., Antonelli, A., & Aloe, L. (2000). NGF expression in the developing rat brain: effects of maternal separation. Brain Research. Developmental Brain Research, 123(2), 129–134.CrossRefGoogle Scholar
  21. 21.
    Williams, L. R., Varon, S., Peterson, G. M., Wictorin, K., Fischer, W., Bjorklund, A., & Gage, F. H. (1986). Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proceedings of the National Academy of Sciences of the United States of America, 83(23), 9231–9235.CrossRefGoogle Scholar
  22. 22.
    Iulita, M. F., & Cuello, A. C. (2014). Nerve growth factor metabolic dysfunction in Alzheimer’s disease and Down syndrome. Trends in Pharmacological Sciences, 35(7), 338–348.  https://doi.org/10.1016/j.tips.2014.04.010.CrossRefGoogle Scholar
  23. 23.
    Capsoni, S., Giannotta, S., & Cattaneo, A. (2002). Beta-amyloid plaques in a model for sporadic Alzheimer’s disease based on transgenic anti-nerve growth factor antibodies. Molecular and Cellular Neurosciences, 21(1), 15–28.CrossRefGoogle Scholar
  24. 24.
    Cattaneo, A., Capsoni, S., & Paoletti, F. (2008). Towards non-invasive nerve growth factor therapies for Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD, 15(2), 255–283.CrossRefGoogle Scholar
  25. 25.
    Origlia, N., Capsoni, S., Domenici, L., & Cattaneo, A. (2006). Time window in cholinomimetic ability to rescue long-term potentiation in neurodegenerating anti-nerve growth factor mice. Journal of Alzheimer’s Disease: JAD, 9(1), 59–68.CrossRefGoogle Scholar
  26. 26.
    Houeland, G., Romani, A., Marchetti, C., Amato, G., Capsoni, S., Cattaneo, A., & Marie, H. (2010). Transgenic mice with chronic NGF deprivation and Alzheimer’s disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 30(39), 13089–13094.  https://doi.org/10.1523/JNEUROSCI.0457-10.2010.CrossRefGoogle Scholar
  27. 27.
    Conner, J. M., Franks, K. M., Titterness, A. K., Russell, K., Merrill, D. A., Christie, B. R., Sejnowski, T. J., & Tuszynski, M. H. (2009). NGF is essential for hippocampal plasticity and learning. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 29(35), 10883–10889.  https://doi.org/10.1523/JNEUROSCI.2594-09.2009.CrossRefGoogle Scholar
  28. 28.
    Covaceuszach, S., Capsoni, S., Ugolini, G., Spirito, F., Vignone, D., & Cattaneo, A. (2009). Development of a non-invasive NGF-based therapy for Alzheimer’s disease. Current Alzheimer Research, 6(2), 158–170.CrossRefGoogle Scholar
  29. 29.
    Marei, H. E., Farag, A., Althani, A., Afifi, N., Abd-Elmaksoud, A., Lashen, S., Rezk, S., Pallini, R., Casalbore, P., & Cenciarelli, C. (2015). Human olfactory bulb neural stem cells expressing hNGF restore cognitive deficit in Alzheimer’s disease rat model. Journal of Cellular Physiology, 230(1), 116–130.  https://doi.org/10.1002/jcp.24688.CrossRefGoogle Scholar
  30. 30.
    Tuszynski, M. H., Thal, L., Pay, M., Salmon, D. P., HS, U., Bakay, R., Patel, P., Blesch, A., Vahlsing, H. L., Ho, G., Tong, G., Potkin, S. G., Fallon, J., Hansen, L., Mufson, E. J., Kordower, J. H., Gall, C., & Conner, J. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11(5), 551–555.  https://doi.org/10.1038/nm1239.CrossRefGoogle Scholar
  31. 31.
    Bishop, K. M., Hof er, E. K., Mehta, A., Ramirez, A., Sun, L., Tuszynski, M., & Bartus, R. T. (2008). Therapeutic potential of CERE-110 (AAV2-NGF): targeted, stable, and sustained NGF delivery and trophic activity on rodent basal forebrain cholinergic neurons. Experimental Neurology, 211(2), 574–584.  https://doi.org/10.1016/j.expneurol.2008.03.004.CrossRefGoogle Scholar
  32. 32.
    Karami, A., Eyjolfsdottir, H., Vijayaraghavan, S., Lind, G., Almqvist, P., Kadir, A., Linderoth, B., Andreasen, N., Blennow, K., Wall, A., Westman, E., Ferreira, D., Kristoffersen Wiberg, M., Wahlund, L. O., Seiger, A., Nordberg, A., Wahlberg, L., Darreh-Shori, T., & Eriksdotter, M. (2015). Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer’s disease. Alzheimer’s & Dementia: The Journal Of The Alzheimer’s Association, 11(11), 1316–1328.  https://doi.org/10.1016/j.jalz.2014.11.008.CrossRefGoogle Scholar
  33. 33.
    Garbuzova-Davis, S., Willing, A. E., Zigova, T., Saporta, S., Justen, E. B., Lane, J. C., Hudson, J. E., Chen, N., Davis, C. D., & Sanberg, P. R. (2003). Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. Journal of Hematotherapy & Stem Cell Research, 12(3), 255–270.  https://doi.org/10.1089/152581603322022990.CrossRefGoogle Scholar
  34. 34.
    Passweg, J. R., Baldomero, H., Bregni, M., Cesaro, S., Dreger, P., Duarte, R. F., Falkenburg, J. H., Kroger, N., Farge-Bancel, D., Gaspar, H. B., Marsh, J., Mohty, M., Peters, C., Sureda, A., Velardi, A., Ruiz de Elvira, C., Madrigal, A., & European Group for B, Marrow T. (2013). Hematopoietic SCT in Europe: data and trends in 2011. Bone Marrow Transplantation, 48(9), 1161–1167.  https://doi.org/10.1038/bmt.2013.51.CrossRefGoogle Scholar
  35. 35.
    Yang, W. Z., Zhang, Y., Wu, F., Min, W. P., Minev, B., Zhang, M., Luo, X. L., Ramos, F., Ichim, T. E., Riordan, N. H., & Hu, X. (2010). Safety evaluation of allogeneic umbilical cord blood mononuclear cell therapy for degenerative conditions. Journal of Translational Medicine, 8, 75.  https://doi.org/10.1186/1479-5876-8-75.CrossRefGoogle Scholar
  36. 36.
    Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D., & Ploix, C. C. (2006). CNS immune privilege: hiding in plain sight. Immunological Reviews, 213, 48–65.  https://doi.org/10.1111/j.1600-065X.2006.00441.x.CrossRefGoogle Scholar
  37. 37.
    Harris, D. T., & Rogers, I. (2007). Umbilical cord blood: a unique source of pluripotent stem cells for regenerative medicine. Current Stem Cell Research & Therapy, 2(4), 301–309.CrossRefGoogle Scholar
  38. 38.
    Neuhoff, S., Moers, J., Rieks, M., Grunwald, T., Jensen, A., Dermietzel, R., & Meier, C. (2007). Proliferation, differentiation, and cytokine secretion of human umbilical cord blood-derived mononuclear cells in vitro. Experimental Hematology, 35(7), 1119–1131.  https://doi.org/10.1016/j.exphem.2007.03.019.CrossRefGoogle Scholar
  39. 39.
    Fan, C. G., Zhang, Q. J., Tang, F. W., Han, Z. B., Wang, G. S., & Han, Z. C. (2005). Human umbilical cord blood cells express neurotrophic factors. Neuroscience Letters, 380(3), 322–325.  https://doi.org/10.1016/j.neulet.2005.01.070.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • M. A. Mukhamedyarov
    • 1
  • A. V. Leushina
    • 1
  • A. E. Tikhonova
    • 1
    • 2
  • E. O. Petukhova
    • 1
  • E. E. Garanina
    • 2
  • R. Ben Taleb
    • 1
    • 2
  • M. S. Kaligin
    • 2
  • Y. O. Mukhamedshina
    • 1
    • 2
  • A. A. Rizvanov
    • 2
  • A. L. Zefirov
    • 1
  • R. R. Islamov
    • 1
  1. 1.Kazan State Medical UniversityKazanRussia
  2. 2.Kazan (Volga Region) Federal UniversityKazanRussia

Personalised recommendations