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

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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.

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References

  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. 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Schellenberg GD, Souza ID’, Poorkaj P (2000) The genetics of Alzheimer’s disease. Curr Psychiatry Rep 2:158–164

    Article  CAS  PubMed  Google Scholar 

  6. Rogaeva E, Tandon A, St George-Hyslop PH (2001) Genetic markers in the diagnosis of Alzheimer’s disease. J Alzheimers Dis JAD 3:293–304

    CAS  PubMed  Google Scholar 

  7. Roberts GW, Gentleman SM, Lynch A, Graham DI (1991) Beta A4 amyloid protein deposition in brain after head trauma. Lancet 338:1422–1423

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  17. Andrew PJ, Mayer B (1999) Enzymatic function of nitric oxide synthases. Cardiovasc Res 43:521–531

    Article  CAS  PubMed  Google Scholar 

  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 21:1431–1442

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  20. Cherian L, Hlatky R, Robertson CS (2004) Nitric oxide in traumatic brain injury. Brain Pathol Zurich Switz 14:195–201

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 13:209–214

    Article  CAS  PubMed  Google Scholar 

  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 16:203–212

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 411:390–398

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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. 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

    Article  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 9:1879–1883

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 12:169–178

    Article  CAS  PubMed  Google Scholar 

  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 38:177–205

    Article  CAS  PubMed  Google Scholar 

  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 96:8721–8726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hamm RJ, Dixon CE, Gbadebo DM et al (1992) Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 9:11–20

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  48. Carvalho BS, Irizarry RA (2010) A framework for oligonucleotide microarray preprocessing. Bioinforma Oxf Engl 26:2363–2367. doi:10.1093/bioinformatics/btq431

    Article  CAS  Google Scholar 

  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. 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 397–420

  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

    Article  CAS  Google Scholar 

  52. Valasek MA, Repa JJ (2005) The power of real-time PCR. Adv Physiol Educ 29:151–159. doi:10.1152/advan.00019.20

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Academy of Finland grant EuroEPINOMICS (AP), The Sigrid Juselius Foundation (AP), CIMO (Center for International Mobility) (DM), Foundation for Polish Science grant MPD/2009/4 (KL), National Science Center of Poland grant 2012/05/N/NZ/02500 (DM, KL), and Ministry of Science and Higher Education grant DNP/N119/ESF-EuroEPINOMICS/2012 (KL).

We are very grateful for the constructive comments of Dr. Anna-Kaisa Haapasalo, PhD, on the manuscript.

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Authors and Affiliations

  1. The Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warsaw, Poland

    Diana Miszczuk, Konrad J. Dębski & Katarzyna Lukasiuk

  2. Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P. O. Box 1627, FIN-70 211, Kuopio, Finland

    Diana Miszczuk, Heikki Tanila & Asla Pitkänen

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  1. Diana Miszczuk
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Correspondence to Asla Pitkänen.

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All experiments were carried out in accordance with the European Council Directive (2010/63/EU) and approved by the Animal Ethics Committee of the Provincial Government of Southern Finland.

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Katarzyna Lukasiuk and Asla Pitkänen shared last authorship.

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Miszczuk, D., Dębski, K.J., Tanila, H. et al. Traumatic Brain Injury Increases the Expression of Nos1, Aβ Clearance, and Epileptogenesis in APP/PS1 Mouse Model of Alzheimer’s Disease. Mol Neurobiol 53, 7010–7027 (2016). https://doi.org/10.1007/s12035-015-9578-3

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