@entity28980 reduces hyperphosphorylated tau and improves outcomes after XXXX .

@entity1 @entity1545 @entity131 @entity75 @entity3072 @entity28980 @entity35 @entity21 @entity14827
UNASSIGNED: @entity131 is a common and serious @entity14827 that lacks a pharmaceutical intervention to improve long-term outcome. @entity3072 is implicated in some of the consequences of @entity131 and is a potential pharmacological target. Protein phosphatase 2A is a heterotrimeric protein that regulates key signalling pathways, and protein phosphatase 2A heterotrimers consisting of the PR55 B-subunit represent the major tau phosphatase in the brain. Here we investigated whether @entity131 in @entity35 and @entity1 would induce changes in protein phosphatase 2A and phosphorylated tau, and whether treatment with @entity28980 -a potent PR55 activator-would reduce phosphorylated tau and improve @entity131 outcomes in @entity35 . Ninety young adult male Long-Evans @entity35 were administered either a fluid percussion injury or sham-injury. A proportion of @entity35 were killed at 2, 24, and 72 h post-injury to assess acute changes in protein phosphatase 2A and tau. Other @entity35 were given either @entity28980 or saline-vehicle treatment that was continuously administered via subcutaneous osmotic pump for 12 weeks. Serial magnetic resonance imaging was acquired prior to, and at 1, 4, and 12 weeks post-injury to assess evolving structural @entity75 and @entity21 . Behavioural impairments were assessed at 12 weeks post-injury. The results showed that @entity131 in @entity35 acutely reduced PR55 expression and protein phosphatase 2A activity, and increased the expression of phosphorylated tau and the ratio of phosphorylated tau to total tau. Similar findings were seen in post-mortem brain samples from acute @entity1 @entity131 @entity1 , although many did not reach statistical significance. Continuous @entity28980 treatment for 12 weeks after sham or fluid percussion injury in @entity35 increased protein phosphatase 2A activity and PR55 expression, and reduced the ratio of phosphorylated tau to total tau, attenuated @entity75 , and improved behavioural outcomes in @entity35 given a fluid percussion injury. Notably, total tau levels were decreased in @entity35 12 weeks after fluid percussion injury, and several other factors, including the use of anaesthetic, the length of recovery time, and that some @entity1545 and behavioural dysfunction still occurred in @entity35 treated with @entity28980 must be considered in the interpretation of this study. However, taken together these data suggest protein phosphatase 2A and hyperphosphorylated tau may be involved in the neurodegenerative cascade of @entity131 , and support the potential use of @entity28980 as a novel @entity131 therapy.
