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


RESULTS
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.


CONCLUSIONS
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.
Alejandra
A
Rangel
Brent
B
Race
Katie
K
Phillips
James
J
Striebel
Nancy
N
Kurtz
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA. bchesebro@nih.gov.
Bruce
B
Chesebro
D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008845:Microinjections; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000473:pathology*; D011328:Prions / Q000235:genetics; D012608:Scrapie / Q000378:metabolism
C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018620:PrPSc Proteins; D011328:Prions