Abstract
Traumatic brain injury (TBI) is a major environmental risk factor for subsequent development of Alzheimer disease (AD). Pathological features that are common to AD and many tauopathies are neurofibrillary tangles (NFTs) and neuropil threads composed of hyperphosphorylated tau. Axonal accumulations of total and phospho-tau have been observed within hours to weeks, and intracytoplasmic NFTs have been documented years after severe TBI in humans. We previously reported that controlled cortical impact TBI accelerated tau pathology in young 3xTg-AD mice. Here, we used this TBI mouse model to investigate mechanisms responsible for increased tau phosphorylation and accumulation after brain trauma. We found that TBI resulted in abnormal axonal accumulation of several kinases that phosphorylate tau. Notably, c-Jun N-terminal kinase (JNK) was markedly activated in injured axons and colocalized with phospho-tau. We found that moderate reduction of JNK activity (40%) by a peptide inhibitor, D-JNKi1, was sufficient to reduce total and phospho-tau accumulations in axons of these mice with TBI. Longer-term studies will be required to determine whether reducing acute tau pathology proves beneficial in brain trauma.