Prion pathogenesis is unaltered in a mouse strain with a permeable blood-brain barrier
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Updated: Feb 1, 2026
Analyzing the Permeability of the Blood-Brain Barrier by Microbial Traversal through Microvascular Endothelial Cells
Published on: February 14, 2020
Annika Keller1,2, Mario Nuvolone2,3, Irina Abakumova2
1Department of Neurosurgery, Clinical Neuroscience Centre, University Hospital Zürich, Zürich University, Zürich, Switzerland.
Abstract:
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.
Insights
Transmissible spongiform encephalopathies (TSEs) are prion diseases. This study found that blood-brain barrier permeability does not influence prion disease initiation, even with parenteral exposure, challenging previous assumptions.
Area of Science:
- Neuroscience
- Infectious Diseases
- Biochemistry
Background:
- Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by prions.
- Prions aggregate into a conformationally modified form (PrPSc) of the cellular prion protein (PrPC).
- Natural prion infections occur via extracerebral routes, including dietary and parenteral exposure, necessitating understanding of neuroinvasion pathways.
Purpose of the Study:
- To investigate the role of the blood-brain barrier (BBB) in prion disease propagation.
- To determine if increased BBB permeability affects prion disease incubation periods and initiation.
- To clarify prion neuroinvasion mechanisms following peripheral exposure.
Main Methods:
- Utilized Pdgfbret/ret mice with a genetically engineered, highly permeable blood-brain barrier.
- Administered prions via various routes, including intracerebral and parenteral (e.g., dietary, hormonal).
- Monitored and compared prion disease incubation times between Pdgfbret/ret mice and control littermates.
Main Results:
- Pdgfbret/ret mice exhibited similar prion disease incubation times compared to control mice, irrespective of the prion administration route.
- Increased blood-brain barrier permeability did not accelerate or alter the onset of prion disease.
- Prion disease initiation appears independent of blood-brain barrier integrity.
Conclusions:
- Blood-brain barrier permeability is not a critical factor in the initiation of prion diseases.
- Prion neuroinvasion following peripheral exposure likely occurs through mechanisms independent of BBB integrity.
- These findings challenge the direct role of the BBB in early prion pathogenesis and suggest alternative neuroinvasion pathways.
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