| The microtubule-associated protein tau plays a major role in organizing and maintaining the integrity of the neuronal cytoskeleton. Dysregulation of tau's function has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia and Parkinsonism linked to chromosome 17. Pathologically, AD and the recently described tauopathies are characterized by the presence of intraneuronal fibrillar structures composed of hyperphosphorylated tau. Current research is focused on trying to decipher the mechanisms leading from tau malfunction to aggregation and cell death. The first study of this dissertation examined how tau protein in differentiated SH-SY5Y cells is processed under conditions of oxidative stress. It was demonstrated that oxidative stress can result in cell death through both caspase-dependent and -independent pathways and that tau is a caspase 3 substrate. In the second study, the localization and function of a pathogenic mutant form of tau expressed in immortalized mouse cortical cells was examined, as well as how this mutant tau affected the cell's response to an apoptotic stress. Findings from the second study indicate that mutant R406W tau is differentially localized, more highly phosphorylated at unique sites and has a decreased microtubule-binding ability. The microtubule-binding ability of mutant tau could be partially restored by dephosphorylation. Mutant R406W tau also sensitized cortical cells to undergoing apoptosis when exposed to an osmotic stress. The findings of these two studies will contribute to increasing the understanding of how tau is likely processed under stress conditions that occur in neurodegenerative diseases. Using the model systems presented in these studies may enhance the understanding of the mechanisms leading to tau dysfunction. |
