Findings from experimental models in which human mutant tau is expressed produce additional assistance for this hypothesis. In these models, hyperphosphorylation of tau often precedes axonopathy and degeneration . Consequently, targeting tau either by reducing its phosphorylation state or aggregation has been a concentrate of preclinical therapeutic development for AD and related dementias . Two main mechanisms proposed to underlie tau hyperphosphorylation are aberrant activation of kinases and downregulation of protein phosphatases. Cyclin dependent kinase 5 and its co activator p25 , glycogen synthase kinase 3 , and protein phosphatase 2A have been implicated in hyperphosphorylation of tau in vivo. Other folks just like protein kinase A , extracellular signal regulated kinase 1 2 , and c Jun N terminal kinase have only been shown to regulate tau phosphorylation in vitro. It really is not identified whether or not these kinases and phosphatase contribute to TBI induced tau pathology.
We previously reported that controlled cortical influence TBI accelerated tau pathology in young 3 Tg AD mice . Importantly, the post traumatic tau pathology appeared to become independent of amyloid . Furthermore, TBI induced tauopathy in these mice resembled tau pathology observed in humans in that tau immunoreactivity was evident in each axonal and somatodendritic compartments. In this study, YM201636 supplier we utilized this experimental TBI mouse model to investigate mechanisms responsible for elevated tau phosphorylation following moderately severe brain trauma. We identified JNK to be critically involved in this method. 5 to 7 month old homozygous three Tg AD mice were employed. three Tg AD mice express three mutant human genes: PS1M146V knockin, APPswe, and TauP301L mutations .
three Tg AD mice were derived from the founders received in the Laferla lab PKI-587 due to the fact 2007. There was no evidence of genetic drift. Mice had been housed in common cages in 12 hour light, 12 hour dark cycle and provided meals and water ad libitum. Mice of both sexes were randomly assigned to experimental groups. All experiments were approved by the animal studies committee at Washington University in St. Louis, MO. Controlled Cortical Impact TBI The experimental TBI kinases were performed as previously described . Briefly, a 5 mm craniotomy was performed around the left hemisphere by a motorized trephine. Experimental TBI was induced by impacting a 3.0 mm diameter metal tip onto the cortex. Impact was centered at 3.0 mm anterior to lambda and mm to the left of midline. A 2.
0 mm impact beneath the dura was chosen, as this injury severity not simply final results in moderate damage to the cortex and underlying hippocampus ipsilateral towards the injury, but additionally causes robust total and phosphorylated tau accumulations in injured axons . Sham injured mice went through identical procedures but had been not injured. Duration of anesthesia exposure for sham group was around 15 minutes 1 minute vs. 18 minutes 1 minute for the TBI group.