To test the hypothesis that JNK is engaged in increasing axonal tau phosphorylation and accumulation following TBI in 3 Tg AD mice, we treated mice with a particular purchase Fingolimod peptide inhibitor of JNK, D JNKi1, or get a handle on peptide, D TAT, via intracerebroventricular injection immediately following TBI. N JNKi1 was chosen over the ATP competitive inhibitor of JNK, SP600125, due to its high specificity to JNK and its long half-life. Rats were killed at 24-hours post-injury and their brains were examined by immunohistochemistry. We stained for c jun phosphorylated at Ser 63 to ascertain the extent to which JNK action was inhibited by D JNKi1 treatment, since c jun is really a known major target of JNK. TBI triggered d jun activation in many pericontusional locations, most consistently the ipsilateral thalamus. We consequently quantified p cjun nuclear staining in this region and found that D JNKi1 treatment reduced p c jun immunoreactivity approximately 40% in comparison with D TAT treated mice. APP is just a strong marker of axonal injury, therefore, we stained these minds for APP to measure the effects of JNK inhibition on Plastid the extent of axonal injury. We also stained for APP proteolytic solution AB utilising the 3D6 antibody, which doesn’t recognize APP. DJNKi1 therapy did not significantly affect the degree of axonal injury as determined by the amounts of APP good axonal varicosities in the fimbria/fornix. DJNKi1 therapy appeared to decrease the amounts of 3D6 positive varicosities within the fimbria, but the reduction didn’t reach statistical significance in comparison with N TAT treated mice. This finding isn’t surprising because N JNKi1 continues to be proven to reduce AB production in vitro. We conclude that D JNKi1 didn’t affect the severity of axonal injury in this setting. Even though the D JNKi1 treatment did not fully stop h jun phosphorylation, buy JZL184 we none the less asked if incomplete JNK inhibition was adequate to affect post-traumatic tau pathology in this model. We examined whole tau pathology by staining with a polyclonal antibody that recognizes tau independent of its phosphorylation state. Stereological quantification showed a mild but significant reduction of total taupositive puncta in the ipsilateral fimbria/fornix. As controls, we also quantified total tau positive somata within the tau positive neurites and ipsilateral amygdala in the CA1. Both of these areas exhibited increased complete tau immunoreactivity but lacked p JNK staining following TBI. Needlessly to say, stereological quantification showed similar variety of tau good somata and neurites in the amygdala and CA1 of D JNKi1 and D TAT treated mice. We next studied effects of JNK inhibition on tau phosphorylation applying phospho specific antibodies against tau phosphorylated at Ser 199, Ser 396 and/or Ser 404, and Thr 231. There have been significant reductions of amounts of pS199 positive and PHF1 positive puncta in the ipsilateral fimbria/fornix of D JNKi1 in comparison to D TAT treated mice. Amounts of pT231 positive puncta weren’t statistically different between treatment groups.