TY - JOUR
T1 - Prion pathogenesis is unaltered in a mouse strain with a permeable blood-brain barrier
AU - Keller, Annika
AU - Nuvolone, Mario
AU - Abakumova, Irina
AU - Chincisan, Andra
AU - Reimann, Regina
AU - Avar, Merve
AU - Heinzer, Daniel
AU - Hornemann, Simone
AU - Wagner, Josephin
AU - Kirschenbaum, Daniel
AU - Voigt, Fabian F.
AU - Zhu, Caihong
AU - Regli, Luca
AU - Helmchen, Fritjof
AU - Aguzzi, Adriano
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.ppat.1007424
DO - 10.1371/journal.ppat.1007424
M3 - Article
C2 - 30496289
AN - SCOPUS:85057547468
VL - 14
SP - e1007424
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 11
ER -