Understanding Prion-like Mechanisms of Tauopathy in Traumatic Brain Injury Using Novel in vivo Models

• Author / Creator

  Alyenbaawi, Hadeel E

• Traumatic brain injury (TBI) is broadly acknowledged as a source of mortality and disability worldwide. It is one of the key risk factors resulting in neurodegeneration and the development of dementia. TBI has been shown to be associated with diseases such as chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD). Both diseases are classified as tauopathies, characterized by a distinct accumulation of abnormally phosphorylated tau protein. In TBI and other tauopathies, the pathology in patients seems to progress to connected brain regions at later stages of the disease, mimicking the spreading mechanisms seen in prion diseases. These prion-like characteristics, specifically the seeding and transmission of tau protein, in CTE and TBI have begun to be elucidated recently by a limited number of in vitro and in vivo studies. However, there is still a lack of information regarding the exact mechanisms of prion-like spreading of tau and the factors influencing it, especially how cells take up the tau seeds in TBI. Also, there is a lack of access to in vivo models to analyze prion-like mechanisms, especially ones which could also be used for high-throughput screening. Our aim is to understand the prion-like mechanism of the pathology of tau protein spreading in TBI patients by establishing a novel TBI paradigm to use in a zebrafish larvae model, as well as engineering a novel tau protein biosensor in transparent zebrafish that can be used to report tau seeding and spreading in vivo. We successfully isolated a stable transgenic zebrafish line that expresses a tauopathy biosensor reporter protein and validated that our transgenic zebrafish can report various forms of tau seeds via intraventricular injections. The biosensor output reports tau aggregation as GFP+ve puncta. Then, we developed an elegantly simple system to induce traumatic brain injury to the tau biosensor larvae and
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  validated the presence of various markers associated with traumatic brain injury including seizure, axonal damage, cell death, hemorrhage, and vasospasm. Additionally, larvae subjected to the blast injury formed GFP+ve puncta, indicative of tau aggregation in their brains and spinal cord at various time points. Further, we uncovered a link between the presence of post-traumatic seizure (PTS) and increased formation of tau aggregates. We also evaluated the impact of seizure activity on tau protein pathology in our TBI model via the use of convulsant and anti-convulsant drugs. We found that both the anticonvulsant drug retigabine and the convulsant drug 4-AP inhibited tau protein accumulation in our TBI model. Lastly, the pharmacological inhibition of dynamin- dependent endocytosis significantly reduced tau protein aggregation in our TBI model, hence demonstrating the important role of dynamin in the uptake of tau seeds and spreading of tau protein in TBI. The engineering of our novel tau protein biosensor and establishment of the TBI model in larval zebrafish will not only uncover more information about the prion-like spreading of tau protein pathology in tauopathies and TBI, but will also provide a valuable model for drug screening and intervention.

• Subjects / Keywords

  • Prion-like
  • Tauopathy
  • Traumatic Brain Injury

• Graduation date

  Spring 2020

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-rj63-pj15

• License

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