Published: November 09, 2018A history of traumatic brain injury (TBI) is linked to later neurodegeneration, with a key feature accumulation of hyperphosphorylated tau. Tau is a microtubule stability protein that undergoes frequent cycles of phosphorylation and dephosphorylation due to kinases and phosphatase activity. Hyperphosphorylation of tau destabilizes microtubules interrupting axonal transport, as well as promotes aggregation disturbing synaptic dysfunction. Aberrant phosphorylation of tau post-injury is thought to be a key player in later neurodegeneration. However, it is not known whether type of TBI- a single severe injury compared to repeated mild injuries- affects the time course of tau accumulation or the pattern of changes in kinases and phosphatases that facilitate this phosphorylation. To investigate, male Sprague Dawley rats were subjected to either a single moderate/severe or 3 mild TBIs spaced 5 days apart (rmTBI) utlising the Marmarou impact-acceleration model. Levels of cortical ptau (AT180, pSer422, oligomeric tau), pGSK3β, pCDK5, pERK1/2, pAkt and PP2Ac were evaluated at 24h, 7 days, 1 month and 3 months post-injury, with changes in tau phosphorylation confirmed via immunohistochemistry. A similar time course of AT180 tau phosphorylation was seen irrespective of the nature of the initiating insult, with a spike at 24h post-injury return to baseline and then increasing chronically at 3 months post-injury. In line with this, levels of PP2Ac were decreased at 24h and 3 months post-injury, indicating a potential loss of phosphatase activity. Interestingly, minimal changes were seen in the kinases examined, with a spike in phosphorylation of GSK3β, at the
inhibitory Ser site, at 24h and 3 months following rmTBI, but not single moderate severe TBI, suggesting a possible protective effect only post-rmTBI. This study highlights that changes in levels of phosphorylated tau are similar, regardless of the initiating injury, and highlights the need to further understand the driving mechanisms behind this phenomenon.Lyndsey Collins-Praino, Daniel Gutschmidt, Jessica Sharkey, Alina Arulsamy, and Frances Corriga
