Date Published: November 29, 2018
Publisher: Public Library of Science
Author(s): Annika Keller, Mario Nuvolone, Irina Abakumova, Andra Chincisan, Regina Reimann, Merve Avar, Daniel Heinzer, Simone Hornemann, Josephin Wagner, Daniel Kirschenbaum, Fabian F. Voigt, Caihong Zhu, Luca Regli, Fritjof Helmchen, Adriano Aguzzi, Neil A. Mabbott.
Transmissible spongiform encephalopathies (TSEs) are caused by the prion, which consists essentially of PrPSc, an aggregated, conformationally modified form of the cellular prion protein (PrPC). Although TSEs can be experimentally transmitted by intracerebral inoculation, most instances of infection in the field occur through extracerebral routes. The epidemics of kuru and variant Creutzfeldt-Jakob disease were caused by dietary exposure to prions, and parenteral administration of prion-contaminated hormones has caused hundreds of iatrogenic TSEs. In all these instances, the development of postexposure prophylaxis relies on understanding of how prions propagate from the site of entry to the brain. While much evidence points to lymphoreticular invasion followed by retrograde transfer through peripheral nerves, prions are present in the blood and may conceivably cross the blood-brain barrier directly. Here we have addressed the role of the blood-brain barrier (BBB) in prion disease propagation using Pdgfbret/ret mice which possess a highly permeable BBB. We found that Pdgfbret/ret mice have a similar prion disease incubation time as their littermate controls regardless of the route of prion transmission. These surprising results indicate that BBB permeability is irrelevant to the initiation of prion disease, even when prions are administered parenterally.
Transmissible spongiform encephalopathies (TSEs) are progressive, invariably lethal neurodegenerative diseases which include Creutzfeldt–Jakob disease, kuru, fatal familial insomnia and Gerstmann–Sträussler–Scheinker syndrome in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE) in cattle . The infectious agent, termed prion, consists primarily of PrPSc, a conformationally modified form of PrPC, a protein encoded by the gene PRNP . Conversion of PrPC into PrPSc leads to accumulation of insoluble, partially protease-resistant prion protein deposits in the brain parenchyma around neurons and neuronal loss which is accompanied by gliosis and spongiform changes. Deletion of PrPC renders mice resistant to prion infections, indicating that its conversion into PrPC is necessary for the development of disease .
In order to detect any possible role of the BBB in prion pathogenesis we used Pdgfbret/ret mice which express a hypomorphic variant of PDGFB . The cerebrovascular tree in these animals is highly permeable to blood-borne macromolecules, as has been demonstrated in several studies using many orthogonal experimental approaches including immunohistochemistry, spectrophotometry, MRI [10, 11, 19]. Surprisingly, these mice are viable and enjoy an almost-normal life span despite their deeply dysfunctional BBB. These findings made it possible to perform prion infection experiments and study the development of disease over many months.