Distinct patterns of spread of prion infection in brains of mice expressing anchorless or anchored forms of prion protein

In humans and animals, prion protein (PrP) is usually expressed as a glycophosphatidylinositol (GPI)-anchored membrane protein, but anchorless PrP may be pathogenic in humans with certain familial prion diseases. Anchored PrP expressed on neurons mediates spread of prions along axons in the peripher...

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Bibliographic Details
Published in:Acta neuropathologica communications 2014-01, Vol.2 (1), p.8-8, Article 8
Main Authors: Rangel, Alejandra, Race, Brent, Phillips, Katie, Striebel, James, Kurtz, Nancy, Chesebro, Bruce
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - metabolism
Animals
Brain - metabolism
Brain - pathology
Calcium-Binding Proteins - metabolism
Disease Models, Animal
Gene Expression Regulation
Genetic aspects
Glial Fibrillary Acidic Protein - metabolism
Health aspects
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microfilament Proteins - metabolism
Microinjections
Neurons
Neurophysiology
Platelet Endothelial Cell Adhesion Molecule-1 - metabolism
Prion Diseases - pathology
Prions - genetics
PrPSc Proteins - metabolism
Scrapie - metabolism
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Summary:In humans and animals, prion protein (PrP) is usually expressed as a glycophosphatidylinositol (GPI)-anchored membrane protein, but anchorless PrP may be pathogenic in humans with certain familial prion diseases. Anchored PrP expressed on neurons mediates spread of prions along axons in the peripheral and central nervous systems. However, the mechanism of prion spread in individuals expressing anchorless PrP is poorly understood. Here we studied prion spread within brain of mice expressing anchorless or anchored PrP. To create a localized initial point of infection, we microinjected scrapie in a 0.5 microliter volume in the striatum. In this experiment, PrPres and gliosis were first detected in both types of mice at 40 days post-inoculation near the needle track. In mice with anchored PrP, PrPres appeared to spread via neurons to distant connected brain areas by the clinical endpoint at 150 days post-inoculation. This PrPres was rarely associated with blood vessels. In contrast, in mice with anchorless PrP, PrPres spread did not follow neuronal circuitry, but instead followed a novel slower pattern utilizing the drainage system of the brain interstitial fluid (ISF) including perivascular areas adjacent to blood vessels, subependymal areas and spaces between axons in white matter tracts. In transgenic mice expressing anchorless PrP small amyloid-seeding PrPres aggregates appeared to be transported in the ISF, thus spreading development of cerebral amyloid angiopathy (CAA) throughout the brain. Spread of amyloid seeding by ISF may also occur in multiple human brain diseases involving CAA.
ISSN:2051-5960
2051-5960
DOI:10.1186/2051-5960-2-8