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ARS Home Midwest Area Ames, Iowa National Animal Disease Center Virus and Prion Research Research Publications at this Location





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Title:   Author  item
                                            WEST GREENLEE, M - Iowa State Universityitem
                                            LIND, M - Iowa State Universityitem
                                            Kokemuller, Robynitem
                                            MAMMADOVA, N - Iowa State Universityitem
                                            KONDRU, N - Iowa State Universityitem
                                            MANNE, S - Iowa State Universityitem
                                            SMITH, J - Iowa State Universityitem
                                            KANTHASAMY, A - Iowa State Universityitem
                                            Greenlee, Justin
  Submitted to: Prion
                                    Publication Type: Abstract Only
                                    Publication Acceptance Date: 4/4/2016
                                    Publication  Date: N/A
                                    Citation: N/AInterpretive Summary:
                                Technical Abstract: Currently, there is a lack of pathologic landmarks to objectively evaluate the progression of prion disease in vivo. The goal of this work was to determine the temporal relationship between transport of misfolded prion protein to the retina from the brain, accumulation of PrPSc in the retina, the response of the surrounding tissue to PrPSc accumulation and resulting neuronal death in a mouse model of scrapie.

C57Bl/6 mice were inoculated intracranially with RML scrapie. Animals were euthanized and retinal samples collected at 30, 60, 90, 105, 120 days post inoculation (dpi) and at the onset of clinical signs of disease (153 dpi average). Retinal homogenates were prepared for RT-QuIC analysis and whole globes were fixed for standard immunohistochemical analysis. Antibodies against the prion protein (6H4), glial fibrillary acidic protein (GFAP), microglia (Iba-1) and activated microglia (CD68) were used to assess accumulation of PrPSc and the resulting response of retinal tissue. Loss of photoreceptors was used as a measure of neuronal death, and was quantified using nuclear counts on hematoxylin counterstained slides. 

PrPSc seeding activity was first detected using RT-QuIC in all samples at 60 dpi, which was approximately 40% of the total incubation of 153 days. Accumulation of PrPSc with coincident activation of retinal glia was first detected at 90 dpi, which was approximately 60% of the total incubation period. Activation of microglia was first detected at 105 dpi (70% of the total incubation period), but significant neuronal death, measured by loss of photoreceptor cells, was not detectable until 120 dpi, which was approximately 80% of the total incubation period.

Our results demonstrate that by using the retina, we can resolve the temporal separation between several key events in the pathogenesis of prion disease. We have described a model with sufficient temporal resolution to study the relationships between transport, accumulation, resultant tissue activation, and neuronal death. This model can be used to both study the mechanisms that underlie these events and evaluate the anti-prion activity of a variety of compounds in vivo.


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