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Cell Therapy as a Way to Correct Impaired Neurogenesis in the Adult Brain in a Model of Alzheimer’s Disease

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Abstract

This work is based on the hypothesis of an impairment in neurogenesis during aging, which may be one of the causes of neurodegenerative diseases, including Alzheimer’s disease (AD). Uncompensated neuronal death leads to memory loss. There is an opinion that activation of endogenous neurogenesis or cell replacement therapy may be an effective treatment of AD. We used mesenchymal stromal cells (MSCs) isolated from the human umbilical cord Wharton’s jelly, which have a number of significant advantages over MSCs from other tissues. Human MSCs (hMSCs) were transplanted into the frontal cortex of 8–9-month-old female 5XFAD transgenic (Tg) mice, a model of the hereditary AD. To evaluate the effects of such transplantation, spatial memory was analyzed in parallel with morphofunctional characteristics of adult neurogenic niches—the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles of the brain, as well as the brain areas responsible for learning and memory—the temporal cortex and CA1/CA3 fields of the hippocampus, using immunohistochemistry for markers of cell proliferation (BrdU) and neuronal differentiation (nestin, doublecortin, β-3 tubulin, NeuN, MAP2, GFAP). 5XFAD Tg mice were characterized by an impaired SGZ/SVZ ratio of proliferative activity and a reduced neuronal density in the cortex and hippocampus. The positive effect of hMSC treatment on memory and neuronal as well as glial density in the temporal cortex and hippocampal regions manifested itself two months after transplantation. By that time, hMSCs were detected in the brain of Tg mice only. Both in Tg and non-transgenic (nTg) mice treated with hMSCs, the density of BrdU+ cells was increased in the adult neurogenic niches, however only in the hippocampus of Tg mice, there was a reduced number of amyloid plaques and apoptotic cells, as well as an increased density of synaptophysin-immunopositive (SyP+) cells. Thus, the positive effect of hMSCs was manifested in the hippocampus of Tg mice, the structure remote from the frontal cortex, i.e. the transplantation site. Overall, our data indicate a paracrine effect of hMSCs, as well as the validity of the chimeric model and the promising use of MSC therapy in the treatment of AD.

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ACKNOWLEDGMENTS

The authors are grateful to P.V. Nekrasov for technical assistance in conducting experiments. The study was performed on the equipment of the Sector of Optical Microscopy and Spectrophotometry at the Pushchino Research Center for Biological Studies, Russian Academy of Sciences.

Funding

This work was supported by the Russian Science Foundation (project No. 18-15-00392).

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Authors and Affiliations

  1. Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia

    A. V. Chaplygina, D. Y. Zhdanova, V. I. Kovalev, N. I. Medvinskaya & N. V. Bobkova

  2. V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Healthcare of the Russian Federation, Moscow, Russia

    R. A. Poltavtseva

Authors
  1. A. V. Chaplygina
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  2. D. Y. Zhdanova
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  3. V. I. Kovalev
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  4. R. A. Poltavtseva
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  5. N. I. Medvinskaya
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  6. N. V. Bobkova
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Contributions

The idea and experimental design (B.N.V. and P.R.A.); data collection (C.A.V., Z.D.Y., K.V.I., M.N.I., P.R.A.) and processing (B.N.V., K.V.I., Z.D.Y., C.A.V., P.R.A.); cell isolation and culturing (P.R.A.), writing and editing a manuscript (B.N.V., Z.D.Y., K.V.I., P.R.A).

Corresponding author

Correspondence to R. A. Poltavtseva.

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CONFLICT OF INTEREST

The authors declare that they have no conflict of interest, both evident and potential, that would be associated with the publication of this article.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2022, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2022, Vol. 108, No. 1, pp. 59–84https://doi.org/10.31857/S0869813922010046.

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Chaplygina, A.V., Zhdanova, D.Y., Kovalev, V.I. et al. Cell Therapy as a Way to Correct Impaired Neurogenesis in the Adult Brain in a Model of Alzheimer’s Disease. J Evol Biochem Phys 58, 117–137 (2022). https://doi.org/10.1134/S0022093022010112

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  • DOI: https://doi.org/10.1134/S0022093022010112

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