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

Alejandra Rangel,Katie Phillips,Brent Race,Nancy Kurtz,Bruce Chesebro,James Striebel

doi:10.1186/2051-5960-2-8

Abstract

BackgroundIn 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.ResultsTo 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.ConclusionsIn 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.

Highlights

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
Host cellular PrP appears to be involved in transport of prion infectivity along peripheral nerves leading to the CNS [9,10,11,12,13,14,15] as well as along neuroanatomical pathways within the CNS such as the optic tract with multiple neurons and synapses leading from retina to the superior colliculus and optic cortex [14,16,17]
Comparison of limiting dilution scrapie titration in C57BL/ 10SnJ (C57) versus tg44 mice In previous experiments i.c. injection of tg44 mice with 106 ID50 of scrapie strains 22 L or RML resulted in large part of the infection at these lower dilutions might have been initiated by infectivity entering the cerebrospinal fluid (CSF) at the time of injection, rather than by the injection into the brain parenchyma itself

Summary

Introduction

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. We studied prion spread within brain of mice expressing anchorless or anchored PrP. With sophisticated testing, PrPnull mice have detectable deficits in both neurophysiological and memory functions (for review see [3]). These functions appear to be related to the function of PrP in neurons because they can be reversed by expression of PrP in neurons using a neuron-specific transgene [4]. The most striking function of PrP to date is the absolute requirement for PrP expression for susceptibility of animals to prion infection and disease [1]. PrP expression on other cell types such as lymphocytes or hepatocytes does not lead to susceptibility to prion infection [21]

Methods

Results

Discussion

Conclusion