Molecular Neurobiology

, Volume 55, Issue 5, pp 4280–4296 | Cite as

Decrease in Adult Neurogenesis and Neuroinflammation Are Involved in Spatial Memory Impairment in the Streptozotocin-Induced Model of Sporadic Alzheimer’s Disease in Rats

  • Taysa Bervian Bassani
  • Jéssica M. Bonato
  • Meira M. F. Machado
  • Valentín Cóppola-Segovia
  • Eric L. R. Moura
  • Silvio M. Zanata
  • Rúbia M. M. W. Oliveira
  • Maria A. B. F. Vital
Article

Abstract

Early impairments in cerebral glucose metabolism and insulin signaling pathways may participate in the pathogenesis of the sporadic form of Alzheimer’s disease (sAD). Intracerebroventricular (ICV) injections of low doses of streptozotocin (STZ) are used to mimic sAD and study these alterations in rodents. Streptozotocin causes impairments in insulin signaling and has been reported to trigger several alterations in the brain, such as oxidative stress, neuroinflammation, and dysfunctions in adult neurogenesis, which may be involved in cognitive decline and are features of human AD. The aim of the present study was to assess the influence of neuroinflammation on the process of adult neurogenesis and consequent cognitive deficits in the STZ-ICV model of sAD in Wistar rats. Streptozotocin caused an acute and persistent neuroinflammatory response, reflected by reactive microgliosis and astrogliosis in periventricular areas and the dorsal hippocampus, accompanied by a marked reduction of the proliferation of neural stem cells in the dentate gyrus of the hippocampus and subventricular zone. Streptozotocin also reduced the survival, differentiation, and maturation of newborn neurons, resulting in impairments in short-term and long-term spatial memory. These results support the hypothesis that neuroinflammation has a detrimental effect on neurogenesis, and both neuroinflammation and impairments in neurogenesis contribute to cognitive deficits in the STZ-ICV model of sAD.

Keywords

Alzheimer’s disease Neurogenesis Neuroinflammation Streptozotocin Spatial memory 

Notes

Acknowledgements

We thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), and Fundação Araucária for financial support. S.M. Zanata, R.M.M.W. Oliveira, and M.A.B.F. Vital are recipients of CNPq fellowships.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    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 111:347–366. doi: 10.1007/s00702-003-0058-y CrossRefPubMedGoogle Scholar
  2. 2.
    Correia SC, Santos RX, Perry G et al (2011) Insulin-resistant brain state: the culprit in sporadic Alzheimer’s disease? Ageing Res Rev 10:264–273. doi: 10.1016/j.arr.2011.01.001 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Correia SC, Santos RX, Carvalho C et al (2012) Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer’s disease and diabetes interrelation. Brain Res 1441:64–78. doi: 10.1016/j.brainres.2011.12.063 CrossRefPubMedGoogle Scholar
  4. 4.
    Salkovic-Petrisic M, Knezovic A, Hoyer S, Riederer P (2013) What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer's research. J Neural Transm 120:233–252. doi: 10.1007/s00702-012-0877-9 CrossRefPubMedGoogle Scholar
  5. 5.
    Qu ZQ, Zhou Y, Zeng YS et al (2012) Protective effects of a rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat. PLoS One. doi: 10.1371/journal.pone.0029641
  6. 6.
    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
  7. 7.
    Waldau B, Shetty AK (2008) Behavior of neural stem cells in the Alzheimer brain. Cell Mol Life Sci 65:2372–2384. doi: 10.1007/s00018-008-8053-y CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Perry EK, Johnson M, Ekonomou A et al (2012) Neurogenic abnormalities in Alzheimer’s disease differ between stages of neurogenesis and are partly related to cholinergic pathology. Neurobiol Dis 47:155–162. doi: 10.1016/j.nbd.2012.03.033 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ekonomou A, Savva GM, Brayne C et al (2015) Stage-specific changes in neurogenic and glial markers in Alzheimer’s disease. Biol Psychiatry 77:711–719. doi: 10.1016/j.biopsych.2014.05.021 CrossRefPubMedGoogle Scholar
  10. 10.
    Hanson ND, Owens MJ, Nemeroff CB (2011) Depression, antidepressants, and neurogenesis: a critical reappraisal. Neuropsychopharmacology 36:2589–2602. doi: 10.1038/npp.2011.220 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Vadodaria KC, Gage FH (2014) SnapShot: adult hippocampal neurogenesis. Cell 156:1114–1114.e1. doi: 10.1016/j.cell.2014.02.029 CrossRefPubMedGoogle Scholar
  12. 12.
    Rajasekar N, Nath C, Hanif K, Shukla R (2016) Intranasal insulin administration ameliorates streptozotocin (ICV)-induced insulin receptor dysfunction, neuroinflammation, amyloidogenesis, and memory impairment in rats. Mol Neurobiol. doi: 10.1007/s12035-016-0169-8
  13. 13.
    Chen Y, Liang Z, Blanchard J et al (2012) A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol Neurobiol:1–15. doi: 10.1007/s12035-012-8375-5
  14. 14.
    Kraska A, Santin MD, Dorieux O et al (2012) In vivo cross-sectional characterization of cerebral alterations induced by intracerebroventricular administration of streptozotocin. PLoS One 7:1–9. doi: 10.1371/journal.pone.0046196 CrossRefGoogle Scholar
  15. 15.
    Javed H, Khan MM, Ahmad A et al (2012) Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 210:340–352. doi: 10.1016/j.neuroscience.2012.02.046 CrossRefPubMedGoogle Scholar
  16. 16.
    Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 5th edition. San Diego Acad Press. doi: 10.1016/0143-4179(83)90049-5
  17. 17.
    Ishrat T, Hoda MN, Khan MB et al (2009) Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer’s type (SDAT). Eur Neuropsychopharmacol 19:636–647. doi: 10.1016/j.euroneuro.2009.02.002 CrossRefPubMedGoogle Scholar
  18. 18.
    Santiago R, Zaminelli T, Bassani TB et al (2015) The mechanism of antidepressant-like effects of piroxicam in rats. J Pharmacol Pharmacother 6:7–12. doi: 10.4103/0976-500X.149133 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167. doi: 10.1016/0165-0270(85)90031-7 CrossRefPubMedGoogle Scholar
  20. 20.
    Gray JM, Vecchiarelli HA, Morena M et al (2015) Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci 35:3879–3892. doi: 10.1523/JNEUROSCI.2737-14.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    de Bruin NMWJ, Prickaerts J, van Loevezijn A et al (2011) Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiol Learn Mem 96:392–402. doi: 10.1016/j.nlm.2011.06.015 CrossRefPubMedGoogle Scholar
  22. 22.
    Mello-Carpes PB, Izquierdo I (2013) The nucleus of the solitary tract→nucleus paragigantocellularis→locus coeruleus→CA1 region of dorsal hippocampus pathway is important for consolidation of object recognition memory. Neurobiol Learn Mem 100:56–63. doi: 10.1016/j.nlm.2012.12.002 CrossRefPubMedGoogle Scholar
  23. 23.
    Sierksma ASR, Prickaerts J, Chouliaras L et al (2013) Behavioral and neurobiological effects of prenatal stress exposure in male and female APPswe/PS1dE9 mice. Neurobiol Aging 34:319–337. doi: 10.1016/j.neurobiolaging.2012.05.012 CrossRefPubMedGoogle Scholar
  24. 24.
    Carlini EA, Mendes FR (2011) Protocolos em psicofarmacologia comportamental: um guia para o estudo de drogas com ação sobre o SNC, com ênfase nas planas medicinais. Fap-Unifesp, São PauloGoogle Scholar
  25. 25.
    Gomes FV, Llorente R, Del Bel EA et al (2015) Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res 164:155–163. doi: 10.1016/j.schres.2015.01.015 CrossRefPubMedGoogle Scholar
  26. 26.
    Alvarez EO, Beauquis J, Revsin Y et al (2009) Cognitive dysfunction and hippocampal changes in experimental type 1 diabetes. Behav Brain Res 198:224–230. doi: 10.1016/j.bbr.2008.11.001 CrossRefPubMedGoogle Scholar
  27. 27.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. doi: 10.1007/s00401-009-0619-8 CrossRefPubMedGoogle Scholar
  28. 28.
    Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553. doi: 10.1152/physrev.00011.2010 CrossRefPubMedGoogle Scholar
  29. 29.
    Kawabori M, Yenari MA (2014) The role of the microglia in acute CNS injury. Metab Brain Dis:381–392. doi: 10.1007/s11011-014-9531-6
  30. 30.
    Mayer G, Nitsch R, Hoyer S (1990) Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res 532:95–100. doi: 10.1016/0006-8993(90)91747-5 CrossRefPubMedGoogle Scholar
  31. 31.
    Lannert H, Hoyer S (1998) Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208CrossRefPubMedGoogle Scholar
  32. 32.
    Biasibetti R, Tramontina AC, Costa AP 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 236:186–193. doi: 10.1016/j.bbr.2012.08.039 CrossRefPubMedGoogle Scholar
  33. 33.
    Hosseinzadeh S, Zahmatkesh M, Zarrindast MR et al (2013) Elevated CSF and plasma microparticles in a rat model of streptozotocin-induced cognitive impairment. Behav Brain Res 256:503–511. doi: 10.1016/j.bbr.2013.09.019 CrossRefPubMedGoogle Scholar
  34. 34.
    Tu S, Wong S, Hodges JR et al (2015) Lost in spatial translation—a novel tool to objectively assess spatial disorientation in Alzheimer’s disease and frontotemporal dementia. Cortex 67:83–94. doi: 10.1016/j.cortex.2015.03.016 CrossRefPubMedGoogle Scholar
  35. 35.
    Fuster-Matanzo A, Llorens-Martin M, Hernandez F, Avila J (2013) Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches. Mediat Inflamm 2013:260925. doi: 10.1155/2013/260925 CrossRefGoogle Scholar
  36. 36.
    Serrano-Pozo A, Gómez-Isla T, Growdon JH et al (2013) A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 182:2332–2344. doi: 10.1016/j.ajpath.2013.02.031 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Simpson JE, Ince PG, Lace G et al (2010) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31:578–590. doi: 10.1016/j.neurobiolaging.2008.05.015 CrossRefPubMedGoogle Scholar
  38. 38.
    Sharma M, Gupta YK (2001) Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci 68:1021–1029. doi: 10.1016/S0024-3205(00)01005-5 CrossRefPubMedGoogle Scholar
  39. 39.
    Agrawal R, Tyagi E, Shukla R, Nath C (2009) A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology 56:779–787. doi: 10.1016/j.neuropharm.2009.01.005 CrossRefPubMedGoogle Scholar
  40. 40.
    Islam F, Ejaz Ahmed M, Khan MM et al (2013) Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type. Neurochem Int 62:492–501. doi: 10.1016/j.neuint.2013.02.006 CrossRefPubMedGoogle Scholar
  41. 41.
    Wang B, Jin K (2014) Current perspectives on the link between neuroinflammation and neurogenesis. Metab Brain Dis:1–11. doi: 10.1007/s11011-014-9523-6
  42. 42.
    Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S (2008) New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev 59:201–220. doi: 10.1016/j.brainresrev.2008.07.007 CrossRefPubMedGoogle Scholar
  43. 43.
    Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson's disease. Prog Neurobiol 63:71–124. doi: 10.1016/S0301-0082(00)00014-9 CrossRefPubMedGoogle Scholar
  44. 44.
    Durany N, Michel T, Kurt J et al (2000) Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer’s disease brains. Int J Dev Neurosci 18:807–813. doi: 10.1016/s0736-5748(00)00046-0 CrossRefGoogle Scholar
  45. 45.
    Shonesy BC, Thiruchelvam K, Parameshwaran K, et al (2012) Central insulin resistance and synaptic dysfunction in intracerebroventricular-streptozotocin injected rodents Neurobiol aging 33:430.e5–430.e18. doi: 10.1016/j.neurobiolaging.2010.12.002
  46. 46.
    Sim Y-J (2014) Treadmill exercise alleviates impairment of spatial learning ability through enhancing cell proliferation in the streptozotocin-induced Alzheimer’s disease rats. J Exerc Rehabil 10:81–8. Doi: 10.12965/jer.140102
  47. 47.
    Yau SY, Li A, So KF (2015) Involvement of adult hippocampal neurogenesis in learning and forgetting. Neural Plast. doi: 10.1155/2015/717958
  48. 48.
    Lieberwirth C, Pan Y, Liu Y, Zhang Z, Wang Z (2016) Hippocampal adult neurogenesis: its regulation and potential role in spatial learning and memory. Brain Res 1644:127–140. doi: 10.1016/j.brainres.2016.05.015 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Taysa Bervian Bassani
    • 1
  • Jéssica M. Bonato
    • 2
  • Meira M. F. Machado
    • 1
  • Valentín Cóppola-Segovia
    • 3
  • Eric L. R. Moura
    • 1
  • Silvio M. Zanata
    • 3
  • Rúbia M. M. W. Oliveira
    • 2
  • Maria A. B. F. Vital
    • 1
  1. 1.Department of PharmacologyFederal University of ParanáCuritibaBrazil
  2. 2.Department of Pharmacology and TherapeuticsState University of MaringáMaringáBrazil
  3. 3.Department of Basic PathologyFederal University of ParanáCuritibaBrazil

Personalised recommendations