In-situ temporospatial characterization of the glial response to prion infection

Authors: MICHAEL, ALYONA - Iowa State University; Greenlee, Justin; HARM, TYLER - Iowa State University; MOORE, S - Orise Fellow; ZHANG, MIN - Iowa State University; LIND, MELISSA - Iowa State University; WEST GREENLEE, M - Iowa State University; SMITH, JODI - Iowa State University

Submitted to: Veterinary Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/3/2019
Publication Date: 7/22/2019
Citation: Michael, A.V., Greenlee, J.J., Harm, T.A., Moore, S.J., Zhang, M., Lind, M.S., West Greenlee, M.H., Smith, J.D. 2019. In-situ temporospatial characterization of the glial response to prion infection. Veterinary Pathology. 57(1):90-107. https://doi.org/10.1177/0300985819861708.
DOI: https://doi.org/10.1177/0300985819861708

Interpretive Summary: Prion diseases are invariably fatal neurologic diseases for which there is no known prevention or cure. Because of long incubation times and knowledge gaps in how the disease progresses, there is not a well-defined model for testing potential cures or preventative measures. Microglia are cells in the brain that respond to the progression of prion disease. We used assessment of the multiple brain regions over a time course of scrapie progression in infected mice to carefully describe the relationship between microglial activation and markers of neuropathology and inflammation. This work demonstrates the pro-inflammatory nature of microglia in the progression of prion disease. Because mechanisms of neurodegeneration in prion disease are similar to other protein misfolding diseases such as Alzheimer's disease and Parkinson's disease, use of this information could benefit researchers that study other neurodegenerative diseases.

Technical Abstract: Mammalian transmissible spongiform encephalopathies (TSEs) induce marked activation of astrocytes and microglia that precedes neuronal loss and cognitive decline. Investigation of clinical parallels between TSEs and other neurodegenerative protein misfolding diseases, such as Alzheimer’s disease, has revealed similar patterns of neuroinflammatory responses to the accumulation of self-propagating amyloids. The contribution of glial activation to the progression of protein misfolding diseases is controversial, with evidence for mediation of both protective and deleterious effects. Glial populations exhibit a heterogeneous distribution throughout the brain, and are capable of dynamic transitions along a spectrum of functional activation states between pro- and anti-inflammatory polarization extremes. The purpose of this study was to use a mouse model of scrapie (RML) to characterize the neuroinflammatory response to prion infection by evaluating glial activation across 15 brain regions over time, and correlating it to traditional markers of prion neuropathology, including neuropil vacuolation and PrPSc deposition. We used quantitative immunohistochemistry to evaluate glial expression of iNOS and Arg1, markers of classical and alternative glial activation, respectively. Our results indicate progressive upregulation of iNOS in microglia, consistent with a pro-inflammatory phenotype, and a mixed astrocytic profile featuring iNOS expression in white matter tracts and detection of Arg1-positive populations throughout the brain. These data establish a comprehensive temporospatial lesion profile for this infection model, and demonstrate evidence of multiple glial activation states.