Mesenchymal Stem Cells Therapy Improved the Streptozotocin-Induced Behavioral and Hippocampal Impairment in Rats

  • María F. Zappa VillarEmail author
  • Juliette López Hanotte
  • Joaquín Pardo
  • Gustavo R. Morel
  • Guillermo Mazzolini
  • Mariana G. García
  • Paula C. ReggianiEmail author


Sporadic Alzheimer’s disease (sAD) is the most prevalent neurodegenerative pathology with no effective therapy until date. This disease promotes hippocampal degeneration, which in turn affects multiple cognitive domains and daily life activities. In this study, we hypothesized that long-lasting therapy with mesenchymal stem cells (MSC) would have a restorative effect on the behavioral alterations and cognitive decline typical of sAD, as they have shown neurogenic and immunomodulatory activities. To test this, we chronically injected intravenous human MSC in a sAD rat model induced by the intracerebroventricular injection of streptozotocin (STZ). During the last 2 weeks, we performed open field, Barnes maze, and marble burying tests. STZ-treated rats displayed a poor performance in all behavioral tests. Cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble burying behavior, the latter being representative of daily life activities. On the hippocampus, we found that STZ promotes neuronal loss in the Cornus Ammoni (CA1) field and decreased neurogenesis in the dentate gyrus. Also, STZ induced a reduction in hippocampal volume and presynaptic protein levels and an exacerbated microgliosis, relevant AD features. The therapy rescued CA1 neurodegeneration but did not reverse the decrease of immature neurons, suggesting that the therapy effect varied among hippocampal neuronal populations. Importantly, cell therapy ameliorated microgliosis and restored hippocampal atrophy and some presynaptic protein levels in the sAD model. These findings, by showing that intravenous injection of human MSC restores behavioral and hippocampal alterations in experimental sAD, support the potential use of MSC therapy for the treatment of neurodegenerative diseases.


Sporadic Alzheimer’s disease Mesenchymal stem cell Cognitive function Microglia Synaptic proteins 



The authors thank to Dr. Rodolfo G. Goya, Dr. Claudia B. Hereñú, Ms. Natalia S. Scelsio, and Ms. Romina Becerra for technical assistance, Ms. Rosana del Cid for English edition, Mr. Mario R. Ramos for graphic design, and Mr. Oscar Vercellini, Ms. Araceli Bigres, and Mr. Juan Manuel Lofeudo for animal care assistance. GRM, MGG, GM, and PCR are career researchers of the Argentine Research Council (CONICET). JLH is a recipient of CONICET doctoral fellowship. MFZV and JP are recipients of CONICET post-doctoral fellowships.

Funding Information

This work was supported by grant #PICT15-1998 from the Argentine Agency for Science and Technology (ANPCyT) and grant #PIP0570 from CONICET to PCR.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there are no conflicts of interest.

Statement on the Welfare of Animals

All applicable international, national, and/or institutional (INIBIOLP’s Animal Welfare Assurance #A5647-01) guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. IACUC, Protocol #P03-03-2016.

Supplementary material

12035_2019_1729_MOESM1_ESM.docx (100 kb)
ESM 1 (DOCX 99 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute for Biochemical Research (INIBIOLP) - National Scientific and Technical Research Council (CONICET) - School of Medical SciencesNational University of La Plata (UNLP)La PlataArgentina
  2. 2.Gene Therapy Laboratory, IIMT, Facultad de Ciencias BiomédicasCONICET-Universidad AustralBuenos AiresArgentina
  3. 3.Department of Cytology, Histology and Embryology B, School of Medical SciencesUNLPLa PlataArgentina

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