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Cellular prion protein participates in amyloid-? transcytosis across the blood-brain barrier.

ABSTRACT: The blood-brain barrier (BBB) facilitates amyloid-? (A?) exchange between the blood and the brain. Here, we found that the cellular prion protein (PrP(c)), a putative receptor implicated in mediating A? neurotoxicity in Alzheimer's disease (AD), participates in A? transcytosis across the BBB. Using an in vitro BBB model, [(125)I]-A?(1-40) transcytosis was reduced by genetic knockout of PrP(c) or after addition of a competing PrP(c)-specific antibody. Furthermore, we provide evidence that PrP(c) is expressed in endothelial cells and, that monomeric A?(1-40) binds to PrP(c). These observations provide new mechanistic insights into the role of PrP(c) in AD.

SUBMITTER: Pflanzner T

PROVIDER: S-EPMC3318156 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Cellular prion protein participates in amyloid-β transcytosis across the blood-brain barrier.

Pflanzner Thorsten T Petsch Benjamin B André-Dohmen Bettina B Müller-Schiffmann Andreas A Tschickardt Sabrina S Weggen Sascha S Stitz Lothar L Korth Carsten C Pietrzik Claus U CU

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20120201 4

The blood-brain barrier (BBB) facilitates amyloid-β (Aβ) exchange between the blood and the brain. Here, we found that the cellular prion protein (PrP(c)), a putative receptor implicated in mediating Aβ neurotoxicity in Alzheimer's disease (AD), participates in Aβ transcytosis across the BBB. Using an in vitro BBB model, [(125)I]-Aβ(1-40) transcytosis was reduced by genetic knockout of PrP(c) or after addition of a competing PrP(c)-specific antibody. Furthermore, we provide evidence that PrP(c) ...[more]

PMID: 22293988

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Project description:BackgroundImpairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases. In prion disease, increased BBB permeability was reported 40 years ago, yet the mechanisms behind the loss of BBB integrity have never been explored. Recently, we showed that reactive astrocytes associated with prion diseases are neurotoxic. The current work examines the potential link between astrocyte reactivity and BBB breakdown.ResultsIn prion-infected mice, the loss of BBB integrity and aberrant localization of aquaporin 4 (AQP4), a sign of retraction of astrocytic endfeet from blood vessels, were noticeable prior to disease onset. Gaps in cell-to-cell junctions along blood vessels, together with downregulation of Occludin, Claudin-5 and VE-cadherin, which constitute tight and adherens junctions, suggested that loss of BBB integrity is linked with degeneration of vascular endothelial cells. In contrast to cells isolated from non-infected adult mice, endothelial cells originating from prion-infected mice displayed disease-associated changes, including lower levels of Occludin, Claudin-5 and VE-cadherin expression, impaired tight and adherens junctions, and reduced trans-endothelial electrical resistance (TEER). Endothelial cells isolated from non-infected mice, when co-cultured with reactive astrocytes isolated from prion-infected animals or treated with media conditioned by the reactive astrocytes, developed the disease-associated phenotype observed in the endothelial cells from prion-infected mice. Reactive astrocytes were found to produce high levels of secreted IL-6, and treatment of endothelial monolayers originating from non-infected animals with recombinant IL-6 alone reduced their TEER. Remarkably, treatment with extracellular vesicles produced by normal astrocytes partially reversed the disease phenotype of endothelial cells isolated from prion-infected animals.ConclusionsTo our knowledge, the current work is the first to illustrate early BBB breakdown in prion disease and to document that reactive astrocytes associated with prion disease are detrimental to BBB integrity. Moreover, our findings suggest that the harmful effects are linked to proinflammatory factors secreted by reactive astrocytes.

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Cellular prion protein participates in amyloid-? transcytosis across the blood-brain barrier.

Publications

Cellular prion protein participates in amyloid-β transcytosis across the blood-brain barrier.

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