Date Published: April 5, 2016
Publisher: Public Library of Science
Author(s): James A. Carroll, James F. Striebel, Alejandra Rangel, Tyson Woods, Katie Phillips, Karin E. Peterson, Brent Race, Bruce Chesebro, Jason Bartz.
Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice.
Several neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD) and prion diseases are characterized by accumulation of aggregates of misfolded protein in brain . The particular protein or proteins involved in each of these diseases are different, but in each disease the protein misfolding appears to be spread within the brain by a seeding process where one misfolded aggregate can seed the misfolding of other normally folded molecules of the same protein by a mechanism known as “seeded polymerization” [2, 3]. In the case of prion diseases, seeded amplification results in increased levels of the misfolded protein and spread to adjacent brain regions. In addition, extracts from these brains can transmit prion disease to new individuals by experimental, iatrogenic or natural routes . The realization that seeded polymerization is a similar process, not only in infectious prion diseases but also in some other non-infectious neurological diseases, has led to a resurgence of interest in studies of prion-like effects in many neurodegenerative diseases . One goal is to develop common strategies of therapeutic intervention against the seeded polymerization events.
In the present work we studied the spread of PrPSc from the injection site in the striatum to several areas distant from this site. Microinjection into a small area made it possible to localize progression of infection over time. Previous studies by others indicated that spread of scrapie infection from the periphery and within the CNS was primarily via nerves using neuroanatomical pathways [40–45]. Here we compared three scrapie strains (22L, ME7 and RML). Outside the striatum, PrPSc from all three strains appeared first on the ipsilateral side in dorsomedial thalamus and lateral cortex , and then sequentially in contralateral cortex and ipsilateral substantia nigra (Fig 4). These findings supported the interpretation that the long distance spread for all three strains was via neural circuitry, and not by the brain interstitial fluid (ISF) as was seen previously over short distances within the striatum .