Traumatic brain injury (TBI) is a prevalent condition worldwide with 1.7 million incidences in the U.S. alone. A range of clinical outcomes have been reported post TBI, including dementia, memory loss, and impaired balance and coordination. The lack FDA approved treatments for TBI drives the need for improved prevention and therapeutic strategies. Finite element (FE) models of brain injury mechanics can be used to advance these efforts. These computational models require appropriate constitutive properties in order to predict accurate brain tissue response to injury loading. Suitable experimental models need to be implemented to match the resolution and computational power of FE models.
The first aim of this thesis was to characterize the mechanical properties of brain tissue. Here, human, porcine, and rat brain tissue mechanical responses to multistep indentation of increasing strains up to 30% strain were recorded. We tested whether the quasilinear theory of viscoelasticity (QLV) was required to capture the mechanical behavior of brain tissue, but observed that linear viscoelasticity was sufficient under the loading condition applied. Using this fitting model, brain tissue stiffness was found to be dependent on anatomical region, loading direction, age, sex and species to varying degrees. This analysis elucidated factors that affect brain tissue injury mechanics and can be used to improve the accuracy of FE models of brain tissue deformation to predict a biofidelic response to TBI.
There is growing evidence linking TBI to pathologies leading to increased risk of neurodegeneration, like tauopathies. However better understanding of these underlying mechanisms is still needed. In our study, we utilized a custom shock tube design to induce blast TBI (bTBI). To isolate the effect of bTBI-induced tau pathology, tau was extracted from sham and shockwave exposed mice 24 hours post injury, referred to as sham and blast tau respectively. We showed that bTBI increased phosphorylation of tau and its propensity to oligomerize. Treatment with blast tau resulted in impaired behavior in mice as well as reduced long term potentiation (LTP) in acute hippocampal slices. Treatment with brain isolate from shockwave exposed tau knockout mice did not exhibit altered behavior or LTP response, eliminating the possibility that any confounding factor in the blast tau preparation was responsible for the impaired outcome. Administration of de-oligomerized blast tau prevented these cognitive impairments, suggesting that toxic effect of blast tau was attributed to its oligomeric form. Here we showed that blast injury can initiate cascades in tau pathology and exposure to this progression results in worsened neurological outcome.
Tau phosphorylation is mainly regulated by protein phosphatase 2A (PP2A), whose activity can be altered by leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1). We sought to leverage this mechanism by infusing LCMT-1 and PME-1 transgenic mice with sham and blast tau. LCMT-1 overexpression prevented behavior and LTP deficits induced by oligomeric blast tau. Furthermore, PME-1 overexpression worsened behavior and LTP response at subthreshold doses of oligomeric blast tau. Together, this illustrated the ability of these two enzymes to regulate the response to exposure of bTBI-induced pathogenic forms of tau. This study indicates the potential of targeting PP2A activity as a viable strategy for therapeutic intervention.
In conclusion, this research expands our understanding of the complexity of brain tissue injury mechanics to inform computational models of TBI, illustrates the deleterious effect of pathogenic forms of tau induced by blast injury on cognitive function, and presents a potential target mechanism for the investigation of therapeutic strategies.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/s20x-pe53 |
| Date | January 2022 |
| Creators | Sundaresh, Sowmya N. |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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