Molecular Neurobiology

, Volume 53, Issue 10, pp 7010–7027 | Cite as

Traumatic Brain Injury Increases the Expression of Nos1, Aβ Clearance, and Epileptogenesis in APP/PS1 Mouse Model of Alzheimer’s Disease

  • Diana Miszczuk
  • Konrad J. Dębski
  • Heikki Tanila
  • Katarzyna Lukasiuk
  • Asla Pitkänen
Article

Abstract

To test the hypothesis that an amyloidogenic genetic background predisposes to worsening of post-TBI outcome, we investigated whether traumatic brain injury (TBI) in amyloid precursor protein (APP)/PS1 mice aggravates epileptogenesis and/or enhances somatomotor and cognitive impairment. To elaborate the mechanisms of worsening outcomes, we studied changes in the expression of genes involved in APP processing and Tau pathways in the perilesional cortex, ipsilateral thalamus, and ipsilateral hippocampus 16 weeks post-TBI. Mild (mTBI) or severe TBI (sTBI) was triggered using controlled cortical impact in 3-month-old APP/PS1 mice and wild-type (Wt) littermates. Morris water-maze revealed a genotype effect on spatial learning and memory as APP/PS1-sTBI mice performed more poorly than Wt-sTBI mice (p < 0.05). Epileptogenesis was affected by genotype and TBI as 88 % of APP/PS1-sTBI mice had epilepsy compared to 11 % in Wt-sTBI (genotype effect p < 0.01) or 50 % in APP/PS1-sham groups (TBI effect p < 0.05). The higher the seizure frequency, the higher the cortical expression of Nos1 (r = 0.83, p < 0.001) and Mapk3 (r = 0.67, p < 0.001). Immunohistochemical analysis confirmed increased amount of NOS1 protein in neuronal somata and processes in the perilesional cortex in APP/PS1-sTBI mice compared to APP/PS1-sham (p < 0.05) or Wt-sTBI mice (p < 0.01). Motor impairment correlated (p < 0.001) with the increased cortical expression of genes encoding proteins related to β-amyloid (Aβ) clearance, including Clu (r = 0.83), Abca1 (r = 0.78), A2m (r = 0.76), Apoe (r = 0.70), and Ctsd (r = 0.63). Immunohistochemical analysis revealed a focal reduction in Aβ load lateral to lesion core in APP/PS1-sTBI mice compared to APP/PS1-sham mice (p < 0.05). The present study provides the first comprehensive evidence of exacerbated epileptogenesis and its molecular mechanisms in Alzheimer’s disease (AD)-related genetic background after TBI.

Keywords

Alzheimer’s disease Beta-amyloid Epileptogenesis Nitric oxide synthase 1 Transcriptome Traumatic brain injury 

Supplementary material

12035_2015_9578_MOESM1_ESM.pdf (3.4 mb)
ESM 1(PDF 3474 kb)

References

  1. 1.
    Pitkänen A, Kemppainen S, Ndode-Ekane XE et al (2014) Posttraumatic epilepsy—disease or comorbidity? Epilepsy Behav EB. doi:10.1016/j.yebeh.2014.01.013 Google Scholar
  2. 2.
    Pitkänen A, Bolkvadze T, Immonen R (2011) Anti-epileptogenesis in rodent post-traumatic epilepsy models. Neurosci Lett 497:163–171. doi:10.1016/j.neulet.2011.02.033 CrossRefPubMedGoogle Scholar
  3. 3.
    Van Den Heuvel C, Thornton E, Vink R (2007) Traumatic brain injury and Alzheimer’s disease: a review. Prog Brain Res 161:303–316. doi:10.1016/S0079-6123(06)61021-2 CrossRefGoogle Scholar
  4. 4.
    Johnson VE, Stewart W, Smith DH (2010) Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease? Nat Rev Neurosci 11:361–370. doi:10.1038/nrn2808 PubMedPubMedCentralGoogle Scholar
  5. 5.
    Schellenberg GD, Souza ID’, Poorkaj P (2000) The genetics of Alzheimer’s disease. Curr Psychiatry Rep 2:158–164CrossRefPubMedGoogle Scholar
  6. 6.
    Rogaeva E, Tandon A, St George-Hyslop PH (2001) Genetic markers in the diagnosis of Alzheimer’s disease. J Alzheimers Dis JAD 3:293–304PubMedGoogle Scholar
  7. 7.
    Roberts GW, Gentleman SM, Lynch A, Graham DI (1991) Beta A4 amyloid protein deposition in brain after head trauma. Lancet 338:1422–1423CrossRefPubMedGoogle Scholar
  8. 8.
    Kay AD, Petzold A, Kerr M et al (2003) Alterations in cerebrospinal fluid apolipoprotein E and amyloid beta-protein after traumatic brain injury. J Neurotrauma 20:943–952. doi:10.1089/089771503770195795 CrossRefPubMedGoogle Scholar
  9. 9.
    Noebels J (2011) A perfect storm: converging paths of epilepsy and Alzheimer’s dementia intersect in the hippocampal formation. Epilepsia 52(Suppl 1):39–46. doi:10.1111/j.1528-1167.2010.02909.x CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Roberson ED, Halabisky B, Yoo JW et al (2011) Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J Neurosci Off J Soc Neurosci 31:700–711. doi:10.1523/JNEUROSCI.4152-10.2011 CrossRefGoogle Scholar
  11. 11.
    Holth JK, Bomben VC, Reed JG et al (2013) Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J Neurosci Off J Soc Neurosci 33:1651–1659. doi:10.1523/JNEUROSCI.3191-12.2013 CrossRefGoogle Scholar
  12. 12.
    Teasdale GM, Nicoll JA, Murray G, Fiddes M (1997) Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 350:1069–1071. doi:10.1016/S0140-6736(97)04318-3 CrossRefPubMedGoogle Scholar
  13. 13.
    Alexander S, Kerr ME, Kim Y et al (2007) Apolipoprotein E4 allele presence and functional outcome after severe traumatic brain injury. J Neurotrauma 24:790–797. doi:10.1089/neu.2006.0133 CrossRefPubMedGoogle Scholar
  14. 14.
    Minkeviciene R, Rheims S, Dobszay MB et al (2009) Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci Off J Soc Neurosci 29:3453–3462. doi:10.1523/JNEUROSCI.5215-08.2009 CrossRefGoogle Scholar
  15. 15.
    Bolkvadze T, Pitkänen A (2012) Development of post-traumatic epilepsy after controlled cortical impact and lateral fluid-percussion-induced brain injury in the mouse. J Neurotrauma 29:789–812. doi:10.1089/neu.2011.1954 CrossRefPubMedGoogle Scholar
  16. 16.
    Calabrese V, Mancuso C, Calvani M et al (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8:766–775. doi:10.1038/nrn2214 CrossRefPubMedGoogle Scholar
  17. 17.
    Andrew PJ, Mayer B (1999) Enzymatic function of nitric oxide synthases. Cardiovasc Res 43:521–531CrossRefPubMedGoogle Scholar
  18. 18.
    Ahn M-J, Sherwood ER, Prough DS et al (2004) The effects of traumatic brain injury on cerebral blood flow and brain tissue nitric oxide levels and cytokine expression. J Neurotrauma 21:1431–1442CrossRefPubMedGoogle Scholar
  19. 19.
    Hall ED, Detloff MR, Johnson K, Kupina NC (2004) Peroxynitrite-mediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury. J Neurotrauma 21:9–20. doi:10.1089/089771504772695904 CrossRefPubMedGoogle Scholar
  20. 20.
    Cherian L, Hlatky R, Robertson CS (2004) Nitric oxide in traumatic brain injury. Brain Pathol Zurich Switz 14:195–201CrossRefGoogle Scholar
  21. 21.
    Deng Y, Thompson BM, Gao X, Hall ED (2007) Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury. Exp Neurol 205:154–165. doi:10.1016/j.expneurol.2007.01.023 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mesenge C, Verrecchia C, Allix M et al (1996) Reduction of the neurological deficit in mice with traumatic brain injury by nitric oxide synthase inhibitors. J Neurotrauma 13:209–214CrossRefPubMedGoogle Scholar
  23. 23.
    Wada K, Chatzipanteli K, Busto R, Dietrich WD (1999) Effects of L-NAME and 7-NI on NOS catalytic activity and behavioral outcome after traumatic brain injury in the rat. J Neurotrauma 16:203–212CrossRefPubMedGoogle Scholar
  24. 24.
    Jankowsky JL, Melnikova T, Fadale DJ et al (2005) Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. J Neurosci Off J Soc Neurosci 25:5217–5224. doi:10.1523/JNEUROSCI.5080-04.2005 CrossRefGoogle Scholar
  25. 25.
    Tajiri N, Kellogg SL, Shimizu T et al (2013) Traumatic brain injury precipitates cognitive impairment and extracellular aβ aggregation in Alzheimer’s disease transgenic mice. PLoS ONE 8, e78851. doi:10.1371/journal.pone.0078851 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mouzon BC, Bachmeier C, Ferro A et al (2014) Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model. Ann Neurol 75:241–254. doi:10.1002/ana.24064 CrossRefPubMedGoogle Scholar
  27. 27.
    Nakagawa Y, Nakamura M, McIntosh TK et al (1999) Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Abeta deposition during aging. J Comp Neurol 411:390–398CrossRefPubMedGoogle Scholar
  28. 28.
    Nakagawa Y, Reed L, Nakamura M et al (2000) Brain trauma in aged transgenic mice induces regression of established abeta deposits. Exp Neurol 163:244–252. doi:10.1006/exnr.2000.7375 CrossRefPubMedGoogle Scholar
  29. 29.
    Hong YT, Veenith T, Dewar D et al (2014) Amyloid imaging with carbon 11-labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurol 71:23–31. doi:10.1001/jamaneurol.2013.4847 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kawai N, Kawanishi M, Kudomi N et al (2013) Detection of brain amyloid β deposition in patients with neuropsychological impairment after traumatic brain injury: PET evaluation using Pittsburgh Compound-B. Brain Inj 27:1026–1031. doi:10.3109/02699052.2013.794963 CrossRefPubMedGoogle Scholar
  31. 31.
    Johnson VE, Stewart W, Smith DH (2011) Widespread Tau and amyloid-beta pathology many years after a single traumatic brain injury in humans. Brain Pathol Zurich Switz. doi:10.1111/j.1750-3639.2011.00513.x Google Scholar
  32. 32.
    Thom M, Liu JYW, Thompson P et al (2011) Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study. Brain J Neurol 134:2969–2981. doi:10.1093/brain/awr209 CrossRefGoogle Scholar
  33. 33.
    Roberson ED, Scearce-Levie K, Palop JJ et al (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754. doi:10.1126/science.1141736 CrossRefPubMedGoogle Scholar
  34. 34.
    Ittner LM, Ke YD, Delerue F et al (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142:387–397. doi:10.1016/j.cell.2010.06.036 CrossRefPubMedGoogle Scholar
  35. 35.
    DeVos SL, Goncharoff DK, Chen G et al (2013) Antisense reduction of tau in adult mice protects against seizures. J Neurosci Off J Soc Neurosci 33:12887–12897. doi:10.1523/JNEUROSCI.2107-13.2013 CrossRefGoogle Scholar
  36. 36.
    Mannix R, Meehan WP, Mandeville J et al (2013) Clinical correlates in an experimental model of repetitive mild brain injury. Ann Neurol 74:65–75. doi:10.1002/ana.23858 CrossRefPubMedGoogle Scholar
  37. 37.
    Hoshino S, Tamaoka A, Takahashi M et al (1998) Emergence of immunoreactivities for phosphorylated tau and amyloid-beta protein in chronic stage of fluid percussion injury in rat brain. Neuroreport 9:1879–1883CrossRefPubMedGoogle Scholar
  38. 38.
    Hawkins BE, Krishnamurthy S, Castillo-Carranza DL et al (2013) Rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury: possible link between traumatic brain injury and sporadic tauopathies. J Biol Chem 288:17042–17050. doi:10.1074/jbc.M113.472746 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jankowsky JL, Fadale DJ, Anderson J et al (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170. doi:10.1093/hmg/ddh019 CrossRefPubMedGoogle Scholar
  40. 40.
    Garcia-Alloza M, Robbins EM, Zhang-Nunes SX et al (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24:516–524. doi:10.1016/j.nbd.2006.08.017 CrossRefPubMedGoogle Scholar
  41. 41.
    Shemer I, Holmgren C, Min R et al (2006) Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors. Eur J Neurosci 23:2035–2047. doi:10.1111/j.1460-9568.2006.04733.x CrossRefPubMedGoogle Scholar
  42. 42.
    Smith DH, Soares HD, Pierce JS et al (1995) A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma 12:169–178CrossRefPubMedGoogle Scholar
  43. 43.
    Nissinen J, Halonen T, Koivisto E, Pitkänen A (2000) A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res 38:177–205CrossRefPubMedGoogle Scholar
  44. 44.
    Scherbel U, Raghupathi R, Nakamura M et al (1999) Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci U S A 96:8721–8726CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hamm RJ, Dixon CE, Gbadebo DM et al (1992) Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 9:11–20CrossRefPubMedGoogle Scholar
  46. 46.
    Bot AM, Dębski KJ, Lukasiuk K (2013) Alterations in miRNA levels in the dentate gyrus in epileptic rats. PLoS ONE 8, e76051. doi:10.1371/journal.pone.0076051 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gentleman RC, Carey VJ, Bates DM et al (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80. doi:10.1186/gb-2004-5-10-r80 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Carvalho BS, Irizarry RA (2010) A framework for oligonucleotide microarray preprocessing. Bioinforma Oxf Engl 26:2363–2367. doi:10.1093/bioinformatics/btq431 CrossRefGoogle Scholar
  49. 49.
    R Development Core Team (2012) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org/
  50. 50.
    Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman R, Carey VJ, Huber W, et al. (eds) Bioinforma. Comput. Biol. Solut. Using R Bioconductor. Springer New York, pp 397–420Google Scholar
  51. 51.
    Cahoy JD, Emery B, Kaushal A et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci Off J Soc Neurosci 28:264–278. doi:10.1523/JNEUROSCI.4178-07.2008 CrossRefGoogle Scholar
  52. 52.
    Valasek MA, Repa JJ (2005) The power of real-time PCR. Adv Physiol Educ 29:151–159. doi:10.1152/advan.00019.20 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Diana Miszczuk
    • 1
    • 2
  • Konrad J. Dębski
    • 1
  • Heikki Tanila
    • 2
  • Katarzyna Lukasiuk
    • 1
  • Asla Pitkänen
    • 2
  1. 1.The Nencki Institute of Experimental BiologyPolish Academy of SciencesWarsawPoland
  2. 2.Department of Neurobiology, A. I. Virtanen Institute for Molecular SciencesUniversity of Eastern FinlandKuopioFinland

Personalised recommendations