Abstract
Military veterans who experience blast-related traumatic brain injuries often suffer from chronic cognitive and neurobehavioral syndromes. Reports of abnormal tau processing following blast injury have raised concerns that some cases may have a neurodegenerative basis. Rats exposed to repetitive low-level blast exhibit chronic neurobehavioral traits and accumulate tau phosphorylated at threonine 181 (Thr181). Using data previously reported in separate studies we tested the hypothesis that region-specific patterns of Thr181 phosphorylation correlate with behavioral measures also previously determined and reported in the same animals. Elevated p-tau Thr181 in anterior neocortical regions and right hippocampus correlated with anxiety as well as fear learning and novel object localization. There were no correlations with levels in amygdala or posterior neocortical regions. Particularly striking were asymmetrical effects on the right and left hippocampus. No systematic variation in head orientation toward the blast wave seems to explain the laterality. Levels did not correlate with behavioral measures of hyperarousal. Results were specific to Thr181 in that no correlations were observed for three other phospho-acceptor sites (threonine 231, serine 396, and serine 404). No consistent correlations were linked with total tau. These correlations are significant in suggesting that p-tau accumulation in anterior neocortical regions and the hippocampus may lead to disinhibited amygdala function without p-tau elevation in the amygdala itself. They also suggest an association linking blast injury with tauopathy, which has implications for understanding the relationship of chronic blast-related neurobehavioral syndromes in humans to neurodegenerative diseases.
Highlights
Accumulation of abnormally phosphorylated tau is a feature of many human neurodegenerative diseases, collectively referred to as tauopathies [51]
Elevated p‐tau threonine 181 (Thr181) in the anterior neocortex and right hippocampus correlates with behavioral measures of anxiety in blast‐exposed rats Rats exposed to repetitive low-level blast develop chronic cognitive and post-traumatic stress disorder (PTSD)-related behavioral trait that are present for at least 1 year following blast exposure [78, 81]
With the anti p-tau antibody AT270 directed against phospho-Thr181, p-tau was increased in the right hippocampus but not the left hippocampus in all three cohorts
Summary
Accumulation of abnormally phosphorylated tau is a feature of many human neurodegenerative diseases, collectively referred to as tauopathies [51]. In diseases such as Alzheimer’s disease, the frontotemporal dementias and primary age-related tauopathy, these accumulations form a range of aggregated and oligomeric structures, with the best-known example being the neurofibrillary tangle (NFT) [51]. Traumatic brain injury (TBI) is a risk factor for later development of neurodegenerative diseases that may have various underlying pathologies. CTE is most often associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into NFTs, which occur in a characteristic pattern [68]. Computational modeling has further suggested that mechanical strain factors may explain why the pathology is most prominent in the depths of cortical sulci [37]
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