Date of Award
Doctor of Philosophy
Jodi D. Smith
Transmissible spongiform encephalopathies constitute a group of mammalian neurodegenerative protein misfolding disorders, characterized by neuronal loss and gliosis in response to accumulation of an abnormal conformer (PrPsc) of the native cellular prion protein (PrPc). The nature of the local inflammatory response and the potential contributions of microgliosis and astrocytosis to the progression of neuropathology have not been fully resolved. Shifts in microglial and astrocytic immunophenotypes have been demonstrated in other human neurodegenerative protein misfolding diseases. Similarly, we anticipated a fluid glial activation profile, characterized by transitions in phenotype markers and immunoproteasome induction, over the course of prion infection. This dissertation sought to characterize the neuroinflammatory response to prion infection using a murine intracranial infection model.
Successive chromogenic immunolabeling and in-situ hybridization were employed in analyzing expression patterns of glial activation markers and a proteasomal subtype (PSMB10) over the timecourse of infection in a murine scrapie model. Our model successfully recapitulated classical patterns of TSE-associated neuropathology and demonstrated a precocious microglial response, relative to other studies. We also identified an upregulation of the proinflammatory enzyme iNOS in glial populations at late stages of disease incubation. Colocalization analysis of glial cytoplasmic and activation markers allowed us to resolve an astrocyte-associated increase in Arg1 expression in clinical disease, despite lack of significant changes in global Arg1 expression. Although quantification of immunoproteasome subunit PSMB10 expression failed to yield significant temporospatial trends, this analysis characterized baseline expression patterns across 16 brain regions. Combined, these findings constitute a comprehensive in-situ evaluation of glial activation and present techniques novel to prion research.
Michael, Alyona, "In-situ temporospatial characterization of the neuroinflammatory response to prion infection in the murine brain" (2018). Graduate Theses and Dissertations. 16760.