Tau based mechanisms in acquired epilepsy and neurodegeneration post brain injuries

Introduction Epilepsy is a common neurologic disease. Acquired epilepsy is caused by a brain insult (e.g., brain trauma or excitotoxicity); however, there is a latent period from several months-to-years between the insult and onset of the seizure. Mounting evidence indicates that > 50% of epilepsy patients will develop chronic neurodegenerative and neurocognitive co-morbidities. As such, it is particularly important to understand the mechanisms implicated between the brain insult and acquired epilepsy, neurodegeneration, and co-morbidities. Recent studies have suggested that hyperphosphorylated tubulin-associated unit (tau) is implicated in rodent models of epilepsy and Alzheimer’s disease, and in experimental and clinical studies of traumatic brain injury as well. These insults causing acquired epilepsy may be different, but the insults might share common cellular and molecular pathways leading to brain damage and an increase in phosphorylated tau. Thus, phosphorylated tau may represent a novel target to mitigate epilepsy and the associated neurocognitive and emotional symptoms post-brain injury. Inhibition of the pathologic hyperphosphorylated tau by specifically enhancing the activity of tau phosphatase and protein phosphatase 2A (PP2A), and/or genetic inhibition of tau protein expression are effective in suppressing seizures in a number of epilepsy and neurodegenerative animal models. The research highlighted in this thesis determined the tau-based mechanisms in acquired epilepsy and neurodegeneration following brain insults and the effect of these novel tau-targeted therapeutic approaches to clarify the efficacy against epileptogenesis, and the neuropsychiatric and neurodegenerative accompaniments that develop following brain injury. Methods Acquired epilepsy was modeled in adult rats utilizing lateral fluid percussion injury and kainic acid-induced post-status epilepticus (SE), and compared to sham controls. With respect to traumatic brain injury (TBI), adult