Braun, Nicholas2021-06-292021-06-292021-03https://hdl.handle.net/11299/220616University of Minnesota Ph.D. dissertation. March 2021. Major: Biomedical Engineering. Advisor: Patrick Alford. 1 computer file (PDF); iii, 98 pages.Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated traumatic brain injury (TBI). CTE is characterized by an assortment of cognitive and behavioral changes or deficiencies, but its diagnosis can only be confirmed upon autopsy by the presence of neurofibrillary tangles (NFTs) of the protein tau in patients’ brains. While CTE is not the only neurodegenerative disease in which tau accumulates in NFTs, it is unique with respect to the localization of NFTs within the architecture of the brain. In CTE, NFTs tend to cluster in the sulcal depths of the brain or in perivascular regions surrounding blood vessels, as opposed to a more diffuse dispersion of NFTs in the brain, as seen in Alzheimer’s disease. In this work, using computational modeling, we find that the preferred localization of NFTs within the sulcal depths and perivascular regions of CTE patient brains are a result of high deformation during TBI. We provide direct evidence that cell-scale mechanical deformation can elicit tau pathologies and functional synaptic deficits in neurons. The mechanical energy associated with these deformations alone can induce tau mislocalization to dendritic spines in primary hippocampal neurons harvested from neonatal rat pups. These cell-scale changes are mediated by hyperphosphorylation of tau and can be reversed with a genetic tau deletion or through the pharmacological inhibition of GSK3β and CDK5 kinases before injury. Additionally, we investigate the role that neuronal architecture within the brain plays in determining the tauopathic and functional synaptic consequences of TBI. Using a standard viscoelastic solid material model and an image-based quantification of neuronal orientation, we correlated the work density in a neuron during a TBI simulation with experimentally-derived tau mislocalization quantifications. Taken together, the results of this work represent an important step forward in the understanding of the cell-scale consequences of TBI, while also providing a potential therapeutic pathway for the prevention of long-term neurodegenerative consequences of TBI.enchronic traumatic encephalopathytautraumatic brain injuryThesis or Dissertation