Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. In FY13 we studied the formation of the amyloid and non-amyloid forms of disease-associated protease-resistant prion protein (PrPres) in scrapie-infected mice. After scrapie infection in transgenic mice expressing anchorless PrP, amyloid is deposited in brain mainly in the perivascular pattern similar to cerebral amyloid angiopathy (CAA) seen in Alzheimers disease and some genetic brain diseases in humans. In our experiments, PrPres amyloid co-localized with microinjected FITC-ovalbumin, a marker of the brain interstitial fluid (ISF) drainage system, suggesting that distribution of precursors of amyloid PrPres by ISF flow might be a part of the pathogenesis leading to CAA. These studies also demonstrated that PrPres was associated with three types of vessels including capillaries, arteries and veins. In contrast to the results seen in transgenic mice, infection of mice expressing anchored PrP gave rise to non-amyloid PrPres which was not associated with blood vessels or with ISF tracers. In FY13 we also studied the effect of PrP expression on sensitivity to kainate-induced seizures in mice. Previous studies by other groups suggested that PrP knockout mice were more sensitive to such seizures. However, our experiments using studying PrP deletion using three different mouse genetic backgrounds showed that PrP deletion sometimes made mice less sensitive to kainate-induced seizures. Furthermore, using genetic complementation studies in vivo, we found that non-PrP genes in the region flanking the deleted PrP gene appeared to be responsible for the effects which appeared to correlate with PrP deletion.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$899,407
Indirect Cost
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Carroll, James A; Striebel, James F; Rangel, Alejandra et al. (2016) Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains. PLoS Pathog 12:e1005551
Race, Brent; Phillips, Katie; Kraus, Allison et al. (2016) Phosphorylated human tau associates with mouse prion protein amyloid in scrapie-infected mice but does not increase progression of clinical disease. Prion 10:319-30
Striebel, James F; Race, Brent; Carroll, James A et al. (2016) Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice. J Gen Virol 97:1481-7
Chesebro, Bruce; Striebel, James; Rangel, Alejandra et al. (2015) Early Generation of New PrPSc on Blood Vessels after Brain Microinjection of Scrapie in Mice. MBio 6:e01419-15
Carroll, James A; Striebel, James F; Race, Brent et al. (2015) Prion infection of mouse brain reveals multiple new upregulated genes involved in neuroinflammation or signal transduction. J Virol 89:2388-404
Race, Brent; Phillips, Katie; Meade-White, Kimberly et al. (2015) Increased infectivity of anchorless mouse scrapie prions in transgenic mice overexpressing human prion protein. J Virol 89:6022-32
Evans, Leonard H; Boi, Stefano; Malik, Frank et al. (2014) Analysis of two monoclonal antibodies reactive with envelope proteins of murine retroviruses: one pan specific antibody and one specific for Moloney leukemia virus. J Virol Methods 200:47-53
Moore, Roger A; Sturdevant, Dan E; Chesebro, Bruce et al. (2014) Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis. J Proteome Res :
Rangel, Alejandra; Race, Brent; Phillips, Katie et al. (2014) Distinct patterns of spread of prion infection in brains of mice expressing anchorless or anchored forms of prion protein. Acta Neuropathol Commun 2:8
Striebel, James; Race, Brent; Chesebro, Bruce (2013) Prion protein and susceptibility to kainate-induced seizures: Genetic pitfalls in the use of PrP knockout mice. Prion 7:

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