Age-dependent response of CCAAT/enhancer binding proteins following traumatic brain injury in mice.

Exacerbated inflammatory responses have been reported following traumatic injury to the aged brain. The present study was designed to investigate the involvement of the transcription factors belonging to the CCAAT/enhancer binding protein (C/EBP) family that regulate expression of many of the pro-inflammatory genes which show increased expression following injury to the aged brain. Controlled cortical impact injury was induced in adult (5-6 months) and aged (22-24 months) C57/BL6 mice. C/EBP mRNA and protein expression were analyzed in injured cortex at 1, 3, and 7 days post-injury. Expression of C/EBPalpha was reduced relative to baseline at day 1 in both adult and aged mice, whereas, it increased at days 3 and 7 post-injury. No significant differences were observed between adult and aged brain. Upregulation of C/EBPbeta was observed 1 day following injury in both the adult and aged brain, but there were no major age-related differences in mRNA levels. However, there was higher C/EBPbeta protein in the aged brain. C/EBPdelta expression increased beginning 1 day post-injury in both adult and aged brain. In this case, the increase in C/EBPdelta expression was higher in the aged brain than in the adult at all time points studied. Expression of CCAAT/enhancer binding protein homologous protein (CHOP), a transcription factor involved in ER stress and protein unfolding responses, was also up-regulated in response to injury, but CHOP levels were significantly lower in the aged than the adult brain. Based on these results, we conclude that differential expression of C/EBP beta, delta and CHOP might contribute to the hyper-inflammatory response and poor prognosis following traumatic brain injury in the elderly patients. In addition elevated C/EBPdelta levels following TBI in the aged brain may play a role in the link between TBI and Alzheimer's disease.