Interactions of the prion peptide (PrP 106-126) with brain capillary endothelial cells: coordinated cell killing and remodeling of intercellular junctions.
We studied here the interactions of PrP 106-126, a peptide corresponding to the prion protein (PrP) amyloidogenic region, with a blood-brain barrier in vitro model consisting of confluent porcine brain endothelial cells (PBEC). PrP 106-126 interacted selectively with PBEC via their luminal side, and caused cumulative cell death, as shown by lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, Caspase 3 induction and direct cell counting. In addition, PrP 106-126, but not its corresponding scrambled peptide, produced a 50% reduction of the trans-endothelial electrical resistance, while the PBEC maintained confluency. This process was accompanied by a 23% increase of PBEC average size and the selective disappearance from the cell borders of the junction proteins occludin, claudin-5 and VE-cadherin (but not ZO-1), as evaluated by immunostaining. These results fit with a mechanism by which PrP 106-126 initiates a coordinated cell killing process ultimately causing the remaining cells to undergo a coordinated remodeling of the intercellular junctions and an expansion of their cell territory.
Cooper
Itzik
I
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel. itzik.cooper@weizmann.ac.il
Cohen-Kashi Malina
Katayun
K
Cagnotto
Alfredo
A
Bazzoni
Gianfranco
G
Salmona
Mario
M
Teichberg
Vivian I
VI
D000595:Amino Acid Sequence; D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000166:cytology* / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000633:toxicity*; D011328:Prions / Q000235:genetics / Q000633:toxicity*; D011485:Protein Binding / Q000502:physiology; D013552:Swine; D019108:Tight Junctions / Q000378:metabolism
D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126)