Seizures are a druggable mechanistic link between TBI and subsequent tauopathy

Abstract

Traumatic brain injury (TBI) is a prominent risk factor for dementias including tauopathies like chronic traumatic encephalopathy (CTE). The mechanisms that promote prion-like spreading of Tau aggregates after TBI are not fully understood, in part due to lack of tractable animal models. Here, we test the putative role of seizures in promoting the spread of tauopathy. We introduce ‘tauopathy reporter’ zebrafish expressing a genetically encoded fluorescent Tau biosensor that reliably reports accumulation of human Tau species when seeded via intraventricular brain injections. Subjecting zebrafish larvae to a novel TBI paradigm produced various TBI features including cell death, post–traumatic seizures, and Tau inclusions. Bath application of dynamin inhibitors or anticonvulsant drugs rescued TBI-induced tauopathy and cell death. These data suggest a role for seizure activity in the prion-like seeding and spreading of tauopathy following TBI. Further work is warranted regarding anti-convulsants that dampen post-traumatic seizures as a route to moderating subsequent tauopathy.

Non-Rodent Genetic Animal Models for Studying Tauopathy: Review of Drosophila, Zebrafish, and C. elegans Models

“…In particular, the proteasomal activity was shown to be compromised in this model delaying Tau clearance, and induction of autophagy activity was suggested as a potential therapy [170]. Other zebrafish tauopathy models in which human Tau was directly expressed under a pan-neuronal promoter also showed frank phosphorylation of Tau, but other classical tauopathy phenotypes were either vague or undetectable in these models [171][172][173][174][175]. The reason for this inconsistency is not clear, but the expression level of Tau protein may be a key difference.…”

“…Compared to the non-disease condition, the microglia in the zebrafish tauopathy model became highly mobile and dynamically changed their morphology with a fewer and shorter branching: more interestingly, the phagocytosis process by the microglia engulfing apoptotic neurons was also observed in real time, and furthermore, the genetic ablation of microglia increased the Tau hyperphosphorylation level, suggesting that microglia possesses a neuroprotective role in the tauopathy condition [195]. Also, as traumatic brain injury (TBI) is a conspicuous risk factor for dementias including Tauopathies, subjecting a novel TBI paradigm to the human Tau WT zebrafish larval model increased neuronal death and Tau inclusion of which phenotypes were rescued by dynamin inhibitors or anticonvulsant drugs [175], suggesting that the seizure activity has the strong impact on prion-like seeding and spreading of Tau following TBI.…”

A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury

“…Traumatic brain injury (TBI) is an important risk factor for neurodegeneration and dementia, such as chronic traumatic encephalopathy (CTE). The primary mechanisms that have much in common in the neuropathology in TBI and CTE patients involve hyperphosphorylated Tau pathology, axonal degeneration, neuronal loss and seizure [ 14 – 16 ]. In this regard, PP2A/B55α expression is reduced in a rat model of repeated mild TBI and restoring its expression with sodium selenite it has been shown to exert neuroprotective effects mitigating hyperphosphorylation of tau [ 17 ].…”

Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis

“…Zebrafish, in contrast, possess region-specific populations of resident quiescent stem cells that are induced by injury to regenerate damaged and lost neurons across the nervous system: olfactory system, retina, spinal cord, and brain [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. The regenerative capacity of the zebrafish brain has been studied following either penetrating TBI, due to either a stab wound or partial excision, by chemical toxins, or ultrasonic or pressure waves [ 24 , 25 , 26 , 27 , 28 , 29 ]. However, the damage in all these models is primarily focal and/or predominately categorized as severe.…”