Author(s)
Ava Dysarz-Sullivan (Student OMS-II)1
Pauline Liu (Student OMS-II)1
Alyssa Seerley
Andrea Grindel
Panter DVM (Faculty)2
Affiliation(s)
1College of Osteopathic Medicine, Touro University Montana, Great Falls, MT2Weissman Hood Research Institute, Great Falls, MT
Abstract:
Prion diseases affect many species, including humans, as a result of misfolding of the prion protein leading to uncurable neurodegeneration. Reports have demonstrated a significantly earlier age of onset and death in females in various prion diseases, yet findings on sex-specific differences in prion diseases have been inconsistent, perhaps due to differences among specific prion diseases and lack of studies designed and powered to specifically address sex differences. Our chosen prion disease model for this study was Chronic Wasting Disease (CWD), a fatal transmissible spongiform encephalopathy affecting cervids caused by misfolding of the prion protein (PrP). Although currently thought to be limited to cervids, CWD shares key pathological features with human neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s disease, and frontotemporal dementia, making it a valuable model for studying mechanisms of neurodegeneration. A longitudinal slope analysis of biomarker to behavior couplings assessing differences between males and females were performed. Investigating sex-specific phenotypes in transgenic mouse lines will aid in determining mechanisms of disease progression, increase diagnostic sensitivity/specificity, and might inform on therapeutic targets. Reliable antemortem diagnostic tools for prion diseases remain extremely limited, highlighting the need for sensitive biomarkers and neurobehavioral profiling that reflect disease progression. In our longitudinal assessment, we recorded home-cage and handling-associated behaviors alongside neurodegeneration markers in male and female transgenic mice inoculated with either normal brain homogenate (NBH) or chronic wasting disease (CWD). Behavioral measures included tail elevation, locomotor activity, balance, and coordination at defined post-inoculation intervals. Disease-related phenotypic differences were exhibited between males and females at matched timepoints of disease. Biomarker analysis revealed that CWD-inoculated mice were more likely to exhibit elevated neurofilament protein levels exceeding the expected normal fit curve, consistent with ongoing axonal injury, and commonly found elevated early and robustly in Alzheimer’s Disease. In contrast, glial fibrillary acidic protein (GFAP) levels showed variable elevation, however, the mean protein concentrations were significantly elevated in diseased animals as opposed to the healthy group. Together, these findings suggest behavioral phenotypes associated with axonal degeneration and gliosis in CWD infection and support the use of combined behavioral and biomarker trajectories to characterize prion disease progression.