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

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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.

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References

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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. 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 12:772–784

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  11. Vadodaria KC, Gage FH (2014) SnapShot: adult hippocampal neurogenesis. Cell 156:1114–1114.e1. doi:10.1016/j.cell.2014.02.029

    Article  CAS  PubMed  Google Scholar 

  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. 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. 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

    Article  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 Paulo

    Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  27. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. doi:10.1007/s00401-009-0619-8

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  Google Scholar 

  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 112:1199–1208

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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. 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. Yau SY, Li A, So KF (2015) Involvement of adult hippocampal neurogenesis in learning and forgetting. Neural Plast. doi:10.1155/2015/717958

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.

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Authors and Affiliations

  1. Department of Pharmacology, Federal University of Paraná, Curitiba, PR, 81540-990, Brazil

    Taysa Bervian Bassani, Meira M. F. Machado, Eric L. R. Moura & Maria A. B. F. Vital

  2. Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, PR, 87020-900, Brazil

    Jéssica M. Bonato & Rúbia M. M. W. Oliveira

  3. Department of Basic Pathology, Federal University of Paraná, Curitiba, PR, 81531-990, Brazil

    Valentín Cóppola-Segovia & Silvio M. Zanata

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  1. Taysa Bervian Bassani
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Correspondence to Taysa Bervian Bassani.

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Bassani, T.B., Bonato, J.M., Machado, M.M.F. et al. 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, 4280–4296 (2018). https://doi.org/10.1007/s12035-017-0645-9

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