PI: T. Wirth

In the first funding period we could demonstrate that NF-κB activity in neurons is required to protect both neurons as well as the animals from death induced by traumatic brain injury (TBI). At the cellular level this could be explained by the initiation of secondary inflammatory processes and upregulation of the pro-apoptotic factors Bad and Bax in NF-κB-inhibited neurons. Work on astrocyte-specific NF-κB modulation revealed a strong effect on the inflammatory parameters, however the acute outcome as measured by a neurological severity scoring system and overall survival was less affected. Interestingly, the activation of NF-κB in oligodendrocytes has a spontaneous inflammatory phenotype, which is currently analyzed. Similarly, activation of NF-κB in myeloid cells including microglia has a spontaneous phenotype. This again is currently investigated in detail. Therefore, we will test in the second funding period, whether the inflammatory responses initiated by NF-κB modulation in oligodendrocytes and microglia differentially regulate TBI outcome. In addition, we will analyze the link between TBI-induced neuroimmune responses and neurodegeneration by studying the contribution of cell-type-specific NF-κB modulation as acceleration/deceleration factor of neurodegenerative processes. In this respect we will also adopt models for repetitive mild TBI to mimic chronic traumatic encephalopathy (CTE). For this task a combination of NF-κB-modulated mice with transgenic APP23 mice, a mouse model of Alzheimer’s disease, will be subjected to TBI and the neurodetrimental consequences will be characterized.