Changes in the localization of brain prion proteins during scrapie infection

Abstract

Prion proteins (PrP) were localized in the brains of normal and scrapie-infected hamsters by immunohistochemistry and Western blotting. PrP monoclonal antibodies and monospecific anti-PrP peptide sera, which react with both the cellular (PrPC) and scrapie (PrPSc) isoforms of the prion protein, were used to locate PrP in tissue sections. In normal hamsters, PrPC was located primarily in nerve cell bodies throughout the CNS; whereas, in the terminal stages of scrapie, PrP immunoreactivity was shifted to the neuropil and was absent from most nerve cell bodies. Prion proteins were not uniformly dispersed throughout the gray matter of scrapie-infected hamster brains; rather, they were concentrated in those regions that exhibited spongiform degeneration and reactive astrogliosis. Since earlier studies showed that the level of PrPC remains constant during scrapie infection as measured in whole brain homogenates and no antibodies are presently available that can distinguish PrPC from PrPSc, we analyzed individual brain regions by Western blotting. Analysis of proteinase K-digested homogenates of dissected brain regions showed that most of the regional changes in PrP immunoreactivity that are seen during scrapie infection are due to the accumulation of PrPSc. These observations indicate that the tissue pathology of scrapie can be directly correlated with the accumulation of PrPSc in the neuropil, and they suggest that the synthesis and distribution of the prion protein has a central role in the pathogenesis of this disorder.

A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brains

“…Earlier studies showed that some PrP Sc is released from degenerating neurons and their processes into the extracellular space of the CNS, where it accumulates in perivascular, subpial, and subependymal spaces (38,39), and is taken up by activated microglia and reactive astrocytes (5,37). Additionally, histoblots indicate that a substantial portion of the residual thalamic PrP Sc is located in large bundles of axons within or immediately adjacent to the thalamus (Fig.…”

Prions

“…Because astrocytic gliosis marked by the deposition of fibrils composed of GFAP is a prominent feature of prion disease (DeArmond et al 1987;Hwang et al 2009), we investigated whether GFAP might be used as a surrogate marker for prions. To interrogate this posit, we inoculated prions into Tg mice expressing luciferase (luc) under the GFAP gene (Gfap) promoter, denoted Tg(Gfap-luc) mice (Tamgüney et al 2009a).…”

The cellular prion protein and its role in Alzheimer disease

“…Sometimes PrP accumulations appear in the form of plaques. 6,7 Based on previous studies carried out in various animals, and knowing that extrapolation is legitimate, a retrograde spread of modified prion proteins from the zone of entry into the nervous system is proposed here. For some authors, such transmission is anterograde; 8 others see it as retrograde [9][10][11] and still others posit a mixed form.…”