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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
Article

Abstract

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.

Keywords

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

Notes

Acknowledgments

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)

References

  1. 1.
    Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509CrossRefGoogle Scholar
  2. 2.
    Gupta S, Yadav K, Mantri SS, Singhal NK, Ganesh S, Sandhir R (2018) Evidence for compromised insulin signaling and neuronal vulnerability in experimental model of sporadic Alzheimer’s disease. Mol Neurobiol 55:8916–8935CrossRefPubMedGoogle Scholar
  3. 3.
    Su L, Hayes L, Soteriades S, Williams G, Brain SAE, Firbank MJ, Longoni G, Arnold RJ et al (2018) Hippocampal Stratum Radiatum, Lacunosum, and Moleculare sparing in mild cognitive impairment. J Alzheimers Dis 61:415–424CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bobinski M, de Leon MJ, Tarnawski M, Wegiel J, Reisberg B, Miller DC, Wisniewski HM (1998) Neuronal and volume loss in CA1 of the hippocampal formation uniquely predicts duration and severity of Alzheimer disease. Brain Res 805:267–269CrossRefPubMedGoogle Scholar
  5. 5.
    West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772CrossRefPubMedGoogle Scholar
  6. 6.
    Llorens-Martín M, Blazquez-Llorca L, Benavides-Piccione R, Rabano A, Hernandez F, Avila J, DeFelipe J (2014) Selective alterations of neurons and circuits related to early memory loss in Alzheimer’s disease. Front Neuroanat 8:38PubMedPubMedCentralGoogle Scholar
  7. 7.
    Grünblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S (2007) Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 101:757–770CrossRefPubMedGoogle Scholar
  8. 8.
    Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl:217–233Google Scholar
  9. 9.
    Shoham S, Bejar C, Kovalev E, Weinstock M (2003) Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol 184:1043–1052CrossRefPubMedGoogle Scholar
  10. 10.
    Shonesy BC, Thiruchelvam K, Parameshwaran K, Rahman EA, Karuppagounder SS, Huggins KW, Pinkert CA, Amin R et al (2012) Central insulin resistance and synaptic dysfunction in intracerebroventricular-streptozotocin injected rodents. Neurobiol Aging 33:430.e5–430.18CrossRefGoogle Scholar
  11. 11.
    Blokland A, Jolles J (1993) Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav 44:491–494CrossRefPubMedGoogle Scholar
  12. 12.
    Blokland A, Jolles J (1994) Behavioral and biochemical effects of an ICV injection of streptozotocin in old Lewis rats. Pharmacol Biochem Behav 47:833–837CrossRefPubMedGoogle Scholar
  13. 13.
    Prickaerts J, Blokland A, Honig W, Meng F, Jolles J (1995) Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-L-carnitine. Brain Res 674:142–146CrossRefPubMedGoogle Scholar
  14. 14.
    Veerendra Kumar MH, Gupta YK (2003) Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer’s disease in rats. Clin Exp Pharmacol Physiol 30:336–342CrossRefPubMedGoogle Scholar
  15. 15.
    Zappa Villar MF, López Hanotte J, Falomir Lockhart E, Trípodi LS, Morel GR, Reggiani PC (2018) Intracerebroventricular streptozotocin induces impaired Barnes maze spatial memory and reduces astrocyte branching in the CA1 and CA3 hippocampal regions. J Neural Transm (Vienna) 125:1787–1803CrossRefGoogle Scholar
  16. 16.
    Rostami F, Javan M, Moghimi A, Haddad-Mashadrizeh A, Fereidoni M (2017) Streptozotocin-induced hippocampal astrogliosis and insulin signaling malfunction as experimental scales for subclinical sporadic Alzheimer model. Life Sci 188:172–185CrossRefPubMedGoogle Scholar
  17. 17.
    Foraker JE, Oh JY, Ylostalo JH, Lee RH, Watanabe J, Prockop DJ (2011) Cross-talk between human mesenchymal stem/progenitor cells (MSCs) and rat hippocampal slices in LPS-stimulated cocultures: the MSCs are activated to secrete prostaglandin E2. J Neurochem 119:1052–1063CrossRefPubMedGoogle Scholar
  18. 18.
    Kwon MS, Noh MY, Oh KW, Cho KA, Kang BY, Kim KS, Kim YS, Kim SH (2014) The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALS patients. J Neurochem 131:206–218CrossRefPubMedGoogle Scholar
  19. 19.
    Sheikh AM, Nagai A, Wakabayashi K, Narantuya D, Kobayashi S, Yamaguchi S, Kim SU (2011) Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: contribution of fractalkine and IL-5. Neurobiol Dis 41:717–724CrossRefPubMedGoogle Scholar
  20. 20.
    Aquino JB, Bolontrade MF, García MG, Podhajcer OL, Mazzolini G (2010) Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma. Gene Ther 17:692–708CrossRefPubMedGoogle Scholar
  21. 21.
    Donega V, Nijboer CH, van Tilborg G, Dijkhuizen RM, Kavelaars A, Heijnen CJ (2014) Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury. Exp Neurol 261:53–64CrossRefPubMedGoogle Scholar
  22. 22.
    Prockop DJ, Oh JY (2012) Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem 113:1460–1469PubMedPubMedCentralGoogle Scholar
  23. 23.
    Baksh D, Yao R, Tuan RS (2007) Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 25:1384–1392CrossRefPubMedGoogle Scholar
  24. 24.
    Bayo J, Fiore E, Aquino JB, Malvicini M, Rizzo M, Peixoto E, Alaniz L, Piccioni F et al (2014) Human umbilical cord perivascular cells exhibited enhanced migration capacity towards hepatocellular carcinoma in comparison with bone marrow mesenchymal stromal cells: a role for autocrine motility factor receptor. Biomed Res Int 2014:837420CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Huang PY, Shih YH, Tseng YJ, Ko TL, Fu YS, Lin YY (2016) Xenograft of human umbilical mesenchymal stem cells from Wharton’s jelly as a potential therapy for rat pilocarpine-induced epilepsy. Brain Behav Immun 54:45–58CrossRefPubMedGoogle Scholar
  26. 26.
    Li J, Yawno T, Sutherland AE, Gurung S, Paton M, McDonald C, Tiwari A, Pham Y et al (2018) Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia. Exp Neurol 308:120–131CrossRefPubMedGoogle Scholar
  27. 27.
    Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE (2005) Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells 23:220–229CrossRefGoogle Scholar
  28. 28.
    Bantubungi K, Blum D, Cuvelier L, Wislet-Gendebien S, Rogister B, Brouillet E, Schiffmann SN (2008) Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington’s disease. Mol Cell Neurosci 37:454–470CrossRefPubMedGoogle Scholar
  29. 29.
    Kim KS, Kim HS, Park JM, Kim HW, Park MK, Lee HS, Lim DS, Lee TH et al (2013) Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer’s disease model. Neurobiol Aging 34:2408–2420CrossRefPubMedGoogle Scholar
  30. 30.
    Lee HJ, Lee JK, Lee H, Carter JE, Chang JW, Oh W, Yang YS, Suh JG et al (2012) 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
  31. 31.
    Song CG, Zhang YZ, Wu HN, Cao XL, Guo CJ, Li YQ, Zheng MH, Han H (2018) Stem cells: a promising candidate to treat neurological disorders. Neural Regen Res 13:1294–1304CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zappa Villar MF, Lehmann M, Garcia MG, Mazzolini G, Morel GR, Console GM, Podhajcer O, Reggiani PC et al (2019) Mesenchymal stem cell therapy improves spatial memory and hippocampal structure in aging rats. Behav Brain Res In Press.  https://doi.org/10.1016/j.bbr.2019.04.001
  33. 33.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  35. 35.
    Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 83:482–504CrossRefGoogle Scholar
  36. 36.
    Dong MX, Li CM, Shen P, Hu QC, Wei YD, Ren YF, Yu J, Gui SW et al (2018) Recombinant tissue plasminogen activator induces long-term anxiety-like behaviors via the ERK1/2-GAD1-GABA cascade in the hippocampus of a rat model. Neuropharmacology 128:119–131CrossRefPubMedGoogle Scholar
  37. 37.
    Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. J Vis Exp 51785Google Scholar
  38. 38.
    Kalueff AV, Tuohimaa P (2005) The grooming analysis algorithm discriminates between different levels of anxiety in rats: potential utility for neurobehavioural stress research. J Neurosci Methods 143:169–177CrossRefPubMedGoogle Scholar
  39. 39.
    Morel GR, Andersen T, Pardo J, Zuccolilli GO, Cambiaggi VL, Hereñú CB, Goya RG (2015) Cognitive impairment and morphological changes in the dorsal hippocampus of very old female rats. Neuroscience 303:189–199CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Locklear MN, Bhamidipaty S, Kritzer MF (2015) Local N-methyl-d-aspartate receptor antagonism in the prefrontal cortex attenuates spatial cognitive deficits induced by gonadectomy in adult male rats. Neuroscience 288:73–85CrossRefPubMedGoogle Scholar
  41. 41.
    Poling A, Cleary J, Monaghan M (1981) Burying by rats in response to aversive and nonaversive stimuli. J Exp Anal Behav 35:31–44CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Bahi A (2016) Sustained lentiviral-mediated overexpression of microRNA124a in the dentate gyrus exacerbates anxiety- and autism-like behaviors associated with neonatal isolation in rats. Behav Brain Res 311:298–308CrossRefPubMedGoogle Scholar
  43. 43.
    Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem 13:655–669CrossRefPubMedGoogle Scholar
  44. 44.
    Pardo J, Uriarte M, Cónsole GM, Reggiani PC, Outeiro TF, Morel GR, Goya RG (2016) Insulin-like growth factor-I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in female aging rats. Eur J Neurosci 44:2120–2128CrossRefPubMedGoogle Scholar
  45. 45.
    West MJ (1993) New stereological methods for counting neurons. Neurobiol Aging 14:275–285CrossRefPubMedGoogle Scholar
  46. 46.
    Diz-Chaves Y, Astiz M, Bellini MJ, Garcia-Segura LM (2013) Prenatal stress increases the expression of proinflammatory cytokines and exacerbates the inflammatory response to LPS in the hippocampal formation of adult male mice. Brain Behav Immun 28:196–206CrossRefPubMedGoogle Scholar
  47. 47.
    Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87:387–406PubMedPubMedCentralGoogle Scholar
  48. 48.
    Isik AT, Celik T, Ural AU, Tosun M, Ulusoy G, Elibol B (2016) Mesenchymal stem cell therapy for the streptozotocin-induced neurodegeneration in rats. Neurol Res 38:364–372CrossRefPubMedGoogle Scholar
  49. 49.
    Mohammadi A, Maleki-Jamshid A, Milan PB, Ebrahimzadeh K, Faghihi F, Joghataei MT (2018) Intrahippocampal transplantation of undifferentiated human chorionic-derived mesenchymal stem cells does not improve learning and memory in the rat model of sporadic Alzheimer disease. Curr Stem Cell Res Ther 14(2):184–190CrossRefGoogle Scholar
  50. 50.
    Cho YH, Kim HS, Lee KH, Lee YE, Chang JW (2006) The behavioral effect of human mesenchymal stem cell transplantation in cold brain injured rats. Acta Neurochir Suppl 99:125–132CrossRefPubMedGoogle Scholar
  51. 51.
    Zappa Villar MF, Lehmann M, García MG, Mazzolini G, Morel GR, Cónsole GM, Podhajcer O, Reggiani PC et al (2019) Mesenchymal stem cell therapy improves spatial memory and hippocampal structure in aging rats. Behav Brain Res 2:111887CrossRefGoogle Scholar
  52. 52.
    Lehmann M, Zappa-Villar MF, García MG, Mazzolini G, Canatelli-Mallat M, Morel GR, Reggiani PC, Goya RG (2019) Umbilical cord cell therapy improves spatial memory in aging rats. Stem Cell Rev 15:612–617.  https://doi.org/10.1007/s12015-019-09895-2 CrossRefPubMedGoogle Scholar
  53. 53.
    Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY et al (2011) Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev 20(8):1297–1308CrossRefPubMedGoogle Scholar
  54. 54.
    Jackson JS, Golding JP, Chapon C, Jones WA, Bhakoo KK (2010) Homing of stem cells to sites of inflammatory brain injury after intracerebral and intravenous administration: a longitudinal imaging study. Stem Cell Res Ther 1(2):17CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wang Y, Han ZB, Ma J, Zuo C, Geng J, Gong W, Sun Y, Li H et al (2012) A toxicity study of multiple-administration human umbilical cord mesenchymal stem cells in cynomolgus monkeys. Stem Cells Dev 3:1401–1408CrossRefGoogle Scholar
  56. 56.
    Sharma A, Sane H, Gokulchandran N, Kulkarni P, Gandhi S, Sundaram J, Paranjape A, Shetty A et al (2015) A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier. Stem Cells Int 2015:905874CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yilmaz G, Vital S, Yilmaz CE, Stokes KY, Alexander JS, Granger DN (2011) Selectin-mediated recruitment of bone marrow stromal cells in the postischemic cerebral microvasculature. Stroke 42(3):806–811CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Wei L, Fraser JL, Lu ZY, Hu X, Yu SP (2012) Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 46(3):635–645CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Edalatmanesh MA, Matin MM, Neshati Z, Bahrami AR, Kheirabadi M (2010) Systemictransplantation of mesenchymal stem cells can reduce cognitive and motor deficits in rats with unilateral lesions of the neostriatum. Neurol Res 32(2):166–172CrossRefPubMedGoogle Scholar
  60. 60.
    Panchenko MM, Poltavtseva RA, Bobkova NV, Vel’meshev DV, Nesterova IV, Samokhin AN, Sukhikh GT (2014) Localization and differentiation pattern of transplanted human multipotent mesenchymal stromal cells in the brain of bulbectomized mice. Bull Exp Biol Med 158:118–122CrossRefPubMedGoogle Scholar
  61. 61.
    Bae KS, Park JB, Kim HS, Kim DS, Park DJ, Kang SJ (2011) Neuron-like differentiation of bone marrow-derived mesenchymal stem cells. Yonsei Med J 52:401–412CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kopen GC, Prockop DJ, Phinney DG (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 96(19):10711–10716CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Qu C, Mahmood A, Lu D, Goussev A, Xiong Y, Chopp M (2008) Treatment of traumatic brain injury in mice with marrow stromal cells. Brain Res 1208:234–239CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Eggenhofer E, Luk F, Dahlke MH, Hoogduijn MJ (2014) The life and fate of mesenchymal stem cells. Front Immunol 5:148CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    English K (2013) Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol 91(1):19–26CrossRefPubMedGoogle Scholar
  66. 66.
    Uccelli A, de Rosbo NK (2015) The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann N Y Acad Sci 1351:114–126CrossRefPubMedGoogle Scholar
  67. 67.
    de Witte SFH, Luk F, Sierra Parraga JM, Gargesha M, Merino A, Korevaar SS, Shankar AS, O'Flynn L et al (2018) Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cells 36(4):602–615CrossRefPubMedGoogle Scholar
  68. 68.
    Walker PA, Shah SK, Jimenez F, Gerber MH, Xue H, Cutrone R, Hamilton JA, Mays RW et al (2010) Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: preserving the blood brain barrier via an interaction with splenocytes. Exp Neurol 225(2):341–352CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Fedotova J, Soultanov V, Nikitina T, Roschin V, Ordyan N, Hritcu L (2016) Ropren® treatment reverses anxiety-like behavior and monoamines levels in gonadectomized rat model of Alzheimer’s disease. Biomed Pharmacother 83:1444–1455CrossRefPubMedGoogle Scholar
  70. 70.
    Hosseinzadeh S, Zahmatkesh M, Heidari M, Hassanzadeh GR, Karimian M, Sarrafnejad A, Zarrindast MR (2015) Hippocampal DHCR24 down regulation in a rat model of streptozotocin-induced cognitive decline. Neurosci Lett 587:107–112CrossRefPubMedGoogle Scholar
  71. 71.
    Bokare AM, Bhonde M, Goel R, Nayak Y (2018) 5-HT6 receptor agonist and antagonist modulates ICV-STZ-induced memory impairment in rats. Psychopharmacology 235:1557–1570CrossRefPubMedGoogle Scholar
  72. 72.
    Ozkay UD, Can OD, Ozkay Y, Oztürk Y (2012) Effect of benzothiazole/piperazine derivatives on intracerebroventricular streptozotocin-induced cognitive deficits. Pharmacol Rep 64:834–847CrossRefPubMedGoogle Scholar
  73. 73.
    Saxena G, Patro IK, Nath C (2011) ICV STZ induced impairment in memory and neuronal mitochondrial function: a protective role of nicotinic receptor. Behav Brain Res 224:50–57CrossRefPubMedGoogle Scholar
  74. 74.
    Deacon RMJ, Rawlins JNP (2005) Hippocampal lesions, species-typical behaviours and anxiety in mice. Behav Brain Res 156:241–249CrossRefPubMedGoogle Scholar
  75. 75.
    Deacon RM (2006) Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protoc 1:122–124CrossRefPubMedGoogle Scholar
  76. 76.
    Kim TK, Han HE, Kim H, Lee JE, Choi D, Park WJ, Han PL (2012) Expression of the plant viral protease NIa in the brain of a mouse model of Alzheimer’s disease mitigates Aβ pathology and improves cognitive function. Exp Mol Med 44:740–748CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Guo Z, Chen Y, Mao YF, Zheng T, Jiang Y, Yan Y, Yin X, Zhang B (2017) Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer’s rat model. Sci Rep 7:45971CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Salkovic-Petrisic M, Knezovic A, Osmanovic-Barilar J, Smailovic U, Trkulja V, Riederer P, Amit T, Mandel S et al (2015) Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer’s disease. Life Sci 136:108–119CrossRefPubMedGoogle Scholar
  79. 79.
    Elgh E, Lindqvist Astot A, Fagerlund M, Eriksson S, Olsson T, Näsman B (2006) Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer’s disease. Biol Psychiatry 59:155–161CrossRefPubMedGoogle Scholar
  80. 80.
    Stoub TR, deToledo-Morrell L, Stebbins GT, Leurgans S, Bennett DA, Shah RC (2006) Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 103:10041–10045CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Majkutewicz I, Kurowska E, Podlacha M, Myślińska D, Grembecka B, Ruciński J, Plucińska K, Jerzemowska G et al (2016) Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats. Behav Brain Res 308:24–37CrossRefPubMedGoogle Scholar
  82. 82.
    Lazarov O, Marr RA (2010) Neurogenesis and Alzheimer’s disease: at the crossroads. Exp Neurol 223:267–281CrossRefPubMedGoogle Scholar
  83. 83.
    Bassani TB, Bonato JM, Machado MMF, Cóppola-Segovia V, Moura ELR, Zanata SM, Oliveira RMMW, Vital MABF (2018) Decrease in adult neurogenesis and neuroinflammation are involved in spatial memory impairment in the streptozotocin-induced model of sporadic Alzheimer’s disease in rats. Mol Neurobiol 55:4280–4296PubMedGoogle Scholar
  84. 84.
    Sun P, Knezovic A, Parlak M, Cuber J, Karabeg MM, Deckert J, Riederer P, Hua Q et al (2015) Long-term effects of Intracerebroventricular streptozotocin treatment on adult neurogenesis in the rat hippocampus. Curr Alzheimer Res 12:772–784CrossRefPubMedGoogle Scholar
  85. 85.
    Bronzuoli MR, Iacomino A, Steardo L, Scuderi C (2016) Targeting neuroinflammation in Alzheimer’s disease. J Inflamm Res 9:199–208CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Cameron B, Landreth GE (2010) Inflammation, microglia, and Alzheimer’s disease. Neurobiol Dis 37:503–509CrossRefPubMedGoogle Scholar
  87. 87-.
    Medeiros R, LaFerla FM (2013) Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 239:133–138CrossRefPubMedGoogle Scholar
  88. 88.
    Spangenberg EE, Green KN (2017) Inflammation in Alzheimer’s disease: lessons learned from microglia-depletion models. Brain Behav Immun 61:1–11CrossRefPubMedGoogle Scholar
  89. 89.
    Kraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, Jan C, Chaigneau M et al (2012) In vivo cross-sectional characterization of cerebral alterations induced by intracerebroventricular administration of streptozotocin. PLoS One 7(9):e46196CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Rodrigues L, Dutra MF, Ilha J, Biasibetti R, Quincozes-Santos A, Leite MC, Marcuzzo S, Achaval M et al (2010) Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin. J Neural Transm (Vienna) 117:1295–1305CrossRefGoogle Scholar
  91. 91.
    Weinstock M, Shoham S (2004) Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J Neural Transm (Vienna) 111:347–366CrossRefGoogle Scholar
  92. 92.
    Biasibetti R, Tramontina AC, Costa AP, Dutra MF, Quincozes-Santos A, Nardin P, Bernardi CL, Wartchow KM et al (2013) Green tea (−)epigallocatechin-3-gallate reverses oxidative stress and reduces acetylcholinesterase activity in a streptozotocin-induced model of dementia. Behav Brain Res 1 236(1):186–193CrossRefGoogle Scholar
  93. 93.
    Vijayan VK, Geddes JW, Anderson KJ, Chang-Chui H, Ellis WG, Cotman CW (1991) Astrocyte hypertrophy in the Alzheimer’s disease hippocampal formation. Exp Neurol 112(1):72–78CrossRefPubMedGoogle Scholar
  94. 94.
    Luo XG, Ding JQ, Chen SD (2010) Microglia in the aging brain: relevance to neurodegeneration. Mol Neurodegener 24(5):12CrossRefGoogle Scholar
  95. 95.
    Norden DM, Godbout JP (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39(1):19–34CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2):1181–1194CrossRefPubMedGoogle Scholar
  97. 97.
    Bian P, Ye C, Zheng X, Yang J, Ye W, Wang Y, Zhou Y, Ma H et al (2017) Mesenchymal stem cells alleviate Japanese encephalitis virus-induced neuroinflammation and mortality. Stem Cell Res Ther 8(1):38CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Ohtaki H, Ylostalo JH, Foraker JE, Robinson AP, Reger RL, Shioda S, Prockop DJ. Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses (2008) Proc Natl Acad Sci USA 105(38):14638–14643.Google Scholar
  99. 99.
    Yan K, Zhang R, Sun C, Chen L, Li P, Liu Y, Peng L, Sun H et al (2013) Bone marrow-derived mesenchymal stem cells maintain the resting phenotype of microglia and inhibit microglial activation. PLoS One 8(12):e84116CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Jose S, Tan SW, Ooi YY, Ramasamy R, Vidyadaran S (2014) Mesenchymal stem cells exert anti-proliferative effect on lipopolysaccharide-stimulated BV2 microglia by reducing tumour necrosis factor-α levels. J Neuroinflammation 3(11):149CrossRefGoogle Scholar
  101. 101.
    Le Blanc K, Mougiakakos D (2012) Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12:383–396CrossRefPubMedGoogle Scholar
  102. 102.
    Vercelli A, Mereuta OM, Garbossa D, Muraca G, Mareschi K, Rustichelli D, Ferrero I, Mazzini L et al (2008) Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 31:395–405CrossRefPubMedGoogle Scholar
  103. 103.
    Drommelschmidt K, Serdar M, Bendix I, Herz J, Bertling F, Prager S, Keller M, Ludwig AK et al (2017) Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury. Brain Behav Immun 60:220–232CrossRefPubMedGoogle Scholar
  104. 104.
    Lin W, Xu L, Zwingenberger S, Gibon E, Goodman SB, Li G (2017) Mesenchymal stem cells homing to improve bone healing. J Orthop Translat 9:19–27CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580CrossRefPubMedGoogle Scholar
  106. 106.
    Forner S, Baglietto-Vargas D, Martini AC, Trujillo-Estrada L, LaFerla FM (2017) Synaptic impairment in Alzheimer’s disease: a dysregulated symphony. Trends Neurosci 40:347–357CrossRefPubMedGoogle Scholar
  107. 107.
    Kirvell SL, Esiri M, Francis PT (2006) Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer’s disease. J Neurochem 98:939–950CrossRefPubMedGoogle Scholar
  108. 108.
    Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56:933–944CrossRefPubMedGoogle Scholar
  109. 109.
    Schwab C, Yu S, Wong W, McGeer EG, McGeer PL (2013) GAD65, GAD67, and GABAT immunostaining in human brain and apparent GAD65 loss in Alzheimer’s disease. J Alzheimers Dis 33:1073–1088CrossRefPubMedGoogle Scholar
  110. 110.
    Südhof TC (2013) Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80:675–690CrossRefPubMedGoogle Scholar
  111. 111.
    Zhang R, Zhao M, Ji HJ, Yuan YH, Chen NH (2013) Study on the dynamic changes in synaptic vesicle-associated protein and axonal transport protein combined with LPS neuroinflammation model. ISRN Neurol 2013:496079CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Rodrigues Hell RC, Silva Costa MM, Goes AM, Oliveira AL (2009) Local injection of BDNF producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion. Neurobiol Dis 33:290–300CrossRefPubMedGoogle Scholar
  113. 113.
    Ojo B, Rezaie P, Gabbott PL, Davies H, Colyer F, Cowley TR, Lynch M, Stewart MG (2012) Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL. Brain Behav Immun 26:778–788CrossRefPubMedGoogle Scholar
  114. 114.
    Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980CrossRefPubMedGoogle Scholar
  115. 115.
    Jiang T, Yu JT, Tan L (2012) Novel disease-modifying therapies for Alzheimer’s disease. J Alzheimers Dis 31:475–492CrossRefPubMedGoogle Scholar
  116. 116.
    Perry VH, O’Connor V (2010) The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective. ASN Neuro 2:e00047CrossRefPubMedGoogle Scholar
  117. 117.
    Pourbadie HG, Sayyah M, Khoshkholgh-Sima B, Choopani S, Nategh M, Motamedi F, Shokrgozar MA (2018) Early minor stimulation of microglial TLR2 and TLR4 receptors attenuates Alzheimer’s disease-related cognitive deficit in rats: behavioral, molecular, and electrophysiological evidence. Neurobiol Aging 70:203–216CrossRefPubMedGoogle Scholar
  118. 118.
    Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212CrossRefPubMedGoogle Scholar
  119. 119.
    Nakano M, Nagaishi K, Konari N, Saito Y, Chikenji T, Mizue Y, Fujimiya M (2016) Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Sci Rep 22(6):24805CrossRefGoogle Scholar
  120. 120.
    Kubota K, Nakano M, Kobayashi E, Mizue Y, Chikenji T, Otani M, Nagaishi K, Fujimiya M (2018) An enriched environment prevents diabetes-induced cognitive impairment in rats by enhancing exosomal miR-146a secretion from endogenous bone marrow-derived mesenchymal stem cells. PLoS One 13(9):e0204252CrossRefPubMedPubMedCentralGoogle Scholar

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© 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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