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

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.