| Filamentous tau inclusions in neurons, astrocytes and oligodendrocytes are the neuropathological hallmark of both sporadic and familial tauopathies. The identification of pathogenic tau mutations in familial tsuopathies, termed frontotemporal dementia with parkinsonism linked to chromosome-17, provide unequivocal support for the hypothesis that defects in the tau gene are sufficient alone to cause neurodegeneration. While the role of deposition of filamentous tau aggregates in neurons as well as neuron loss in the neurodegenerative process is largely accepted, the relative contribution of the glial pathology is mostly unknown. The purpose of the studies presented in this dissertation is to better understand the role of astrocytic tau pathology in neuronal dysfunction and consequential development of neurodegeneration. First, we examined the role of heat shock proteins (HSPs) to disease pathogenesis of tauopathies with abundant glial pathology. We demonstrate increased expression of the small HSP, alphaB-crystallin specifically in glial tau inclusions of both sporadic and familial tauopathies suggesting a specific response by glia to the accumulation of misfolded protein. Secondly, to better understand the functional contribution of astrocytic tau pathology to disease pathogenesis, we developed the first transgenic mouse model of tau expression restricted to astrocytes. These Tg mice manifest an age-dependent accumulation of tau pathology in astrocytes similar to the human disease. We also demonstrate functional consequences of this pathology including reduced expression and activity of the filial glutamate transporters, GLT-1 and GLAST that correlated with compromised motor function. Thus, the GFAP/tau Tg mice suggest a role for altered astrocyte function in disease pathogenesis. Lastly, we generated mixed astrocyte/neuron cultures from the GFAP/tau Tg mice to assess the consequences of astrocytic tau expression on neuron survival. In mixed cultures generated from GFAP/tau Tg mice, we demonstrate reduced neuron survival that was blocked by NMDA receptor antagonists indicative of glutamate-mediated excitotoxicity. In conclusion, these studies propose that distinct mechanisms underlie the pathogenesis of glial versus neuronal tau pathology in tauopathies. It provides a better understanding of the significance of astrocytic tau pathology to the process of neurodegeneration. More importantly, they elucidate novel pathways that contribute to the disease pathogenesis of tauopathies. |
