Journal of Molecular Neuroscience

, Volume 55, Issue 4, pp 1006–1013 | Cite as

Mesenchymal Stem Cells Can Prevent Alterations in Behavior and Neurogenesis Induced by Aß25–35 Administration

  • Keren Nicole Hamisha
  • Matanel Tfilin
  • Joseph Yanai
  • Gadi Turgeman


Mesenchymal stem cells (MSCs) are known to enhance neurogenesis in the dentate gyrus, as well as to modulate immune cell activity and inflammation. Easily obtained and expanded from the bone marrow and other tissues, MSCs have been proposed as candidates for stem cell therapy in various neurodegenerartive diseases. In the present study, we sought to explore these therapeutic properties of MSC on Aß25–35-induced pathology when coadministered together. Apparently, coadministration of MSC prevented mild cognitive deficits observed following Aß administration alone, by promoting microglial activation and rapid clearance of injected Aß aggregates. Surprisingly, increased hippocampal neurogenesis was observed in the Aß-injected animals and was normal in MSC-coadministered animals just as in control animals. The observed increase in neurogenesis can be explained as a compensating mechanism responsible for the mild and temporary cognitive deficits observed in the Morris water maze assay in Aß-injected animals. Interestingly, MSC engrafted not only to the hippocampus but were also detected in the choroid plexus. We thus conclude that MSC may act in multiple pathways to protect the CNS from Aß pathology, while neurogenesis is a possible compensating mechanism; it is not always activated by MSC, which in turn may interact with local immune cells to regulate Aß accumulation.


Mesenchymal stem cells 25–35 Hippocampus Neurogenesis Doublecortin (DCX) Spatial learning and memory 


  1. Adeosun SO, Hou X, Zheng B, Stockmeier C, Ou X, Paul I, Mosley T, Weisgraber K, Wang JM (2014) Cognitive deficits and disruption of neurogenesis in a mouse model of apolipoprotein E4 domain interaction. J Biol Chem 289:2946–2959CrossRefPubMedCentralPubMedGoogle Scholar
  2. Bae JS, Jin HK, Lee JK, Richardson JC, Carter JE (2013) Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-beta deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer’s disease. Curr Alzheimers Res 10:524–531CrossRefGoogle Scholar
  3. Balseanu AT, Buga AM, Catalin B, Wagner DC, Boltze J, Zagrean AM, Reymann K, Schaebitz W, Popa-Wagner A (2014) Multimodal approaches for regenerative stroke therapies: combination of granulocyte colony-stimulating factor with bone marrow mesenchymal stem cells is not superior to G-CSF alone. Front Aging Neurosci. doi:10.3389/fnagi.2014.00130 PubMedCentralPubMedGoogle Scholar
  4. Broersen K, Rousseau F, Schymkowitz J (2010) The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer’s disease: oligomer size or conformation? Alzheimers Res Ther 2:12CrossRefPubMedCentralPubMedGoogle Scholar
  5. Coquery N, Blesch A, Stroh A, Fernandez-Klett F, Klein J, Winter C, Priller J (2012) Intrahippocampal transplantation of mesenchymal stromal cells promotes neuroplasticity. Cytotherapy 14:1041–1053CrossRefPubMedGoogle Scholar
  6. Glabe CC (2005) Amyloid accumulation and pathogensis of Alzheimer’s disease: significance of monomeric, oligomeric and fibrillar Abeta. Subcell Biochem 38:167–177CrossRefPubMedGoogle Scholar
  7. Hermann D, Buga AM, Popa-Wagner A (2013) Neurovascular remodeling in the aged ischemic brain. J Neural Transm. doi:10.1007/s00702-013-1148-0 Google Scholar
  8. Jellinger KA, Attems J (2013) Neuropathological approaches to cerebral aging and neuroplasticity. Dialogues Clin Neurosci 15:29–43PubMedCentralPubMedGoogle Scholar
  9. Jin K, Galvan V, Xie L, Mao XO, Gorostiza OF, Bredesen DE, Greenberg DA (2004) Enhanced neurogenesis in Alzheimer’s disease transgenic (PDGF-APPSw, Ind) mice. Proc Natl Acad Sci U S A 101:13363–13367CrossRefPubMedCentralPubMedGoogle Scholar
  10. Kim JY, Kim DH, Kim JH, Lee D, Jeon HB, Kwon SJ, Kim SM, Yoo YJ, Lee EH, Choi SJ, Seo SW, Lee JI, Na DL, Yang YS, Oh W, Chang JW (2012) Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-beta plaques. Cell Death Differ 19:680–691CrossRefPubMedCentralPubMedGoogle Scholar
  11. Koronyo-Hamaoui M, Ko MK, Koronyo Y, Azoulay D, Seksenyan A, Kunis G, Pham M, Bakhsheshian J, Rogeri P, Black KL, Farkas DL, Schwartz M (2009) Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9. J Neurochem 111:1409–1424CrossRefPubMedGoogle Scholar
  12. Kwon SH, Lee HK, Kim JA, Hong SI, Kim SY, Jo TH, Park YI, Lee CK, Kim YB, Lee SY, Jang CG (2011) Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta(25–35) induced learning and memory impairments in mice. Neurosci Lett 487:123–127CrossRefPubMedGoogle Scholar
  13. Lee JK, Jin HK, Js B (2009) Bone marrow-derived mesenchymal stem cells reduce brain amyloid-[beta] deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model. Neurosci Lett 450:136–141CrossRefPubMedGoogle Scholar
  14. Lee HJ, Lee JK, Lee H, Jw S, Carter JE, Sakamoto T, Jin HK, Js B (2010a) The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer’s disease. Neurosci Lett 481:30–35CrossRefPubMedGoogle Scholar
  15. Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Js B (2010b) Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells 28:329–343PubMedGoogle Scholar
  16. Lee HJ, Lee JK, Lee H, Carter JE, Chang JW, Oh W, Yang YS, Suh JG, Lee BH, Jin HK, Js B (2012a) Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through modulation of neuroinflammation. Neurobiol Aging 33:588–602CrossRefPubMedGoogle Scholar
  17. Lee JK, Schuchman EH, Jin HK, Bae JS (2012b) Soluble CCL5 derived from bone marrow-derived mesenchymal stem cells and activated by amyloid b ameliorates Alzheimer’s disease in mice by recruiting bone marrow-induced microglia immune responses. Stem Cells 30:1544–1555CrossRefPubMedGoogle Scholar
  18. Maurice T, Lockhart BP, Privat A (1996) Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193CrossRefPubMedGoogle Scholar
  19. Moon M, Cha MY, Mook-Jung I (2014) Impaired Hippocampal neurogenesis and its enhancement with Ghrelin in 5XFAD mice. J Alzheimers Dis 41:233–241PubMedGoogle Scholar
  20. Mu Y, Gage F (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener 6:85CrossRefPubMedCentralPubMedGoogle Scholar
  21. Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ (2005) Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci U S A 102:18171–18176CrossRefPubMedCentralPubMedGoogle Scholar
  22. Oh SH, Kim HN, Park HJ, Shin JY, Lee PH (2014) Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the Wnt signaling pathway in Alzheimer’s disease model. Cell Transplant. doi:10.3727/096368914X679237 Google Scholar
  23. Pimplikar S (2014) Neuroinflammation in Alzheimer’s disease: from pathogenesis to a therapeutic target. J Clin Immunol 34:64–69CrossRefGoogle Scholar
  24. Schwartz M, Shechter R (2010) Protective autoimmunity functions by intracranial immunosurveillance to support the mind: the missing link between health and disease. Mol Psychiatry 15:342–354CrossRefPubMedGoogle Scholar
  25. Serot JM, Zmudka J, Jouanny P (2012) A possible role for CSF turnover and choroid plexus in the pathogenesis of late onset alzheimer’s disease. J Alzheimers Dis 30:17–26PubMedGoogle Scholar
  26. Shin JY, Park HJ, Kim HN, Oh SH, Bae JS, Ha HJ, Lee PH (2013) Mesenchymal stem cells enhance autophagy and increase beta-amyloid clearance in Alzheimer disease models. Autophagy 10:32–44CrossRefPubMedGoogle Scholar
  27. Shruster A, Offen D (2014) Targeting neurogenesis ameliorates danger assessment in a mouse model of Alzheimer’s disease. Behav Brain Res 261:193–201CrossRefPubMedGoogle Scholar
  28. Tfilin M, Sudai E, Merenlender A, Gispan I, Yadid G, Turgeman G (2010) Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 15:1164–1175CrossRefPubMedGoogle Scholar
  29. Ubhi K, Masliah E (2013) Alzheimer’s disease: recent advances and future perspectives. J Alzheimers Dis 33:S185–S194PubMedGoogle Scholar
  30. Yanai H, Budovsky A, Tacutu R, Fraifeld V (2011) Is rate of skin wound healing associated with aging or longevity phenotype? Biogerontology 12:591–597CrossRefPubMedGoogle Scholar
  31. Yang H, Xie Z, Wei L, Yang H, Yang S, Zhu Z, Wang P, Zhao C, Bi J (2013) Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AbetaPP/PS1 transgenic mouse model. Stem Cell Res Ther 4:76CrossRefPubMedCentralPubMedGoogle Scholar
  32. Yun HM, Kim HS, Park KR, Shin JM, Kang AR, K i L, Song S, Kim YB, Han SB, Chung HM, Hong JT (2013) Placenta-derived mesenchymal stem cells improve memory dysfunction in an A[beta]1-42-infused mouse model of Alzheimer/’s disease. Cell Death Dis 4:e958CrossRefPubMedCentralPubMedGoogle Scholar
  33. Zheng M, Liu J, Ruan Z, Tian S, Ma Y, Zhu J, Li G (2013) Intrahippocampal injection of Ab1-42 inhibits neurogenesis and down-regulates IFN-g and NF-kB expression in hippocampus of adult mouse brain. Amyloid 20:13–20CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Keren Nicole Hamisha
    • 1
    • 2
  • Matanel Tfilin
    • 1
  • Joseph Yanai
    • 2
  • Gadi Turgeman
    • 1
  1. 1.Department of Molecular Biology, Laboratory of Stem Cell Research, Milken CampusAriel UniversityArielIsrael
  2. 2.The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research–Israel-CanadaHebrew University-Hadassah Medical SchoolJerusalemIsrael

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