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


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.


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



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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Ethics Approval

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.

Supplementary material

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


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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

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