PrP Antibodies Do Not Trigger Mouse Hippocampal Neuron Apoptosis

Science ◽  
2012 ◽  
Vol 335 (6064) ◽  
pp. 52-52 ◽  
Author(s):  
Peter-Christian Klöhn ◽  
Michael Farmer ◽  
Jacqueline M. Linehan ◽  
Catherine O'Malley ◽  
Mar Fernandez de Marco ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Surface ◽  
Prion Protein ◽  
Prion Disease ◽  
Hippocampal Neuron ◽  
Intraperitoneal Administration ◽  
Cross Linking ◽  
Intracerebral Injection ◽  
Alzheimer’S Diseases ◽  
Neuron Apoptosis

Intraperitoneal administration of ICSM18 and 35, monoclonal antibodies against prion protein (PrP), has been shown to significantly delay the onset of prion disease in mice, and humanized versions are candidate therapeutics for prion and Alzheimer’s diseases. However, a previous report of severe and widespread apoptosis after intracerebral injection of anti-PrP monoclonal antibodies raised concerns about such therapy and led to an influential model of prion neurotoxicity via cross-linking of cell surface PrP by disease-related PrP aggregates. In extensive studies including ICSM18 and 35, fully humanized ICSM18, and the previously reported proapoptotic antibodies, we found no evidence of apoptosis, thereby questioning this model of prion neurotoxicity.

Decreased cell surface prion protein in mouse models of prion disease

Neuroreport ◽  
2007 ◽  
Vol 18 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Jennifer K. Griffin ◽  
Linda A. Terry ◽  
Roy Jackman ◽  
Masoud Yousefi ◽  
Neil R. Cashman
Keyword(s):  
Cell Surface ◽  
Prion Protein ◽  
Mouse Models ◽  
Prion Disease

scholarly journals Mapping the Prion Protein Using Recombinant Antibodies

1998 ◽  
Vol 72 (11) ◽  
pp. 9413-9418 ◽  
Author(s):  
R. Anthony Williamson ◽  
David Peretz ◽  
Clemencia Pinilla ◽  
Hadyn Ball ◽  
Raiza B. Bastidas ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Surface ◽  
Prion Protein ◽  
Disease Process ◽  
Cellular Prion Protein ◽  
Epitope Region ◽  
Molecular Events ◽  
C Terminus ◽  
Phage Display Libraries ◽  
Recombinant Molecule

ABSTRACT The fundamental event in prion disease is thought to be the posttranslational conversion of the cellular prion protein (PrPC) into a pathogenic isoform (PrPSc). The occurrence of PrPC on the cell surface and PrPSc in amyloid plaques in situ or in aggregates following purification complicates the study of the molecular events that underlie the disease process. Monoclonal antibodies are highly sensitive probes of protein conformation which can be used under these conditions. Here, we report the rescue of a diverse panel of 19 PrP-specific recombinant monoclonal antibodies from phage display libraries prepared from PrP deficient (Prnp0/0) mice immunized with infectious prions either in the form of rods or PrP 27-30 dispersed into liposomes. The antibodies recognize a number of distinct linear and discontinuous epitopes that are presented to a varying degree on different PrP preparations. The epitope reactivity of the recombinant PrP(90-231) molecule was almost indistinguishable from that of PrPC on the cell surface, validating the importance of detailed structural studies on the recombinant molecule. Only one epitope region at the C terminus of PrP was well presented on both PrPC and PrPSc, while epitopes associated with most of the antibodies in the panel were present on PrPCbut absent from PrPSc.

scholarly journals PrP glycoforms are associated in a strain-specific ratio in native PrPSc

2005 ◽  
Vol 86 (9) ◽  
pp. 2635-2644 ◽  
Author(s):  
Azadeh Khalili-Shirazi ◽  
Linda Summers ◽  
Jacqueline Linehan ◽  
Gary Mallinson ◽  
David Anstee ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Normal Brain ◽  
Western Blots ◽  
Prion Strains ◽  
Specific Manner ◽  
First Time

Prion diseases involve conversion of host-encoded cellular prion protein (PrPC) to a disease-related isoform (PrPSc). Using recombinant human β-PrP, a panel of monoclonal antibodies was produced that efficiently immunoprecipitated native PrPSc and recognized epitopes between residues 93–105, indicating for the first time that this region is exposed in both human vCJD and mouse RML prions. In contrast, monoclonal antibodies raised to human α-PrP were more efficient in immunoprecipitating PrPC than PrPSc, and some of them could also distinguish between different PrP glycoforms. Using these monoclonal antibodies, the physical association of PrP glycoforms was studied in normal brain and in the brains of humans and mice with prion disease. It was shown that while PrPC glycoforms can be selectively immunoprecipitated, the differentially glycosylated molecules of native PrPSc are closely associated and always immunoprecipitate together. Furthermore, the ratio of glycoforms comprising immunoprecipitated native PrPSc from diverse prion strains was similar to those observed on denaturing Western blots. These studies are consistent with the view that the proportion of each glycoform incorporated into PrPSc is probably controlled in a strain-specific manner and that each PrPSc particle contains a mixture of glycoforms.

Retrospective Neuropathological Review of Prion Disease in UK Haemophilic Patients

1998 ◽  
Vol 80 (12) ◽  
pp. 909-911 ◽  
Author(s):  
James Ironside ◽  
Jeanne Bell ◽  
Paul Giangrande ◽  
Christopher Ludlam ◽  
Margaret M. Esiri ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Prion Disease ◽  
Clotting Factor ◽  
Spongiform Encephalopathy ◽  
Post Mortem ◽  
Blood Products ◽  
Factor Concentrate ◽  
Donor Source

SummaryIn 1996, the CJD surveillance unit in Edinburgh, UK described nvCJD which was thought to be the human equivalent of bovine spongiform encephalopathy (BSE). The identification of prion protein in the tonsil of an affected individual has raised the question of transmission of nvCJD via blood products. This study examines the post mortem brains of 33 patients who were treated with clotting factor concentrate of predominately UK donor source during the years 1962-1995. The brains were examined by conventional histological methods and also for the prion protein using monoclonal antibodies KG9 and 3F4. No evidence of spongiform encephalopathy was found and the immunocytochemistry was negative for PrP in all cases. It is concluded that, at present, there is no evidence for the transmission of nvCJD via clotting factor concentrate to patients with haemophilia.

scholarly journals Immunohistochemistry for the Prion Protein: Comparison of Different Monoclonal Antibodies in Human Prion Disease Subtypes

2006 ◽  
Vol 12 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Gábor G. Kovács ◽  
Mark W. Head ◽  
Ivan Hegyi ◽  
Tristan J. Bunn ◽  
Helga Flicker ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Prion Protein ◽  
Prion Disease ◽  
Human Prion Disease ◽  
Disease Subtypes

scholarly journals Normal prion protein trafficking in cultured human erythroblasts

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4518-4525 ◽  
Author(s):  
Rebecca E. Griffiths ◽  
Kate J. Heesom ◽  
David J. Anstee
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Prion Protein ◽  
Protein Trafficking ◽  
Prion Diseases ◽  
Cross Linking ◽  
Red Cell ◽  
Jakob Disease ◽  
Endosomal Pathway ◽  
Tetraspanin Cd63

Normal prion protein (PrPc), an essential substrate for development of prion disease, is widely distributed in hematopoietic cells. Recent evidence that variant Creutzfeldt-Jakob disease can be transmitted by transfusion of red cell preparations has highlighted the need for a greater understanding of the biology of PrPc in blood and blood-forming tissues. Here, we show that in contrast to another glycosylphosphoinositol-anchored protein CD59, PrPc at the cell surface of cultured human erythroblasts is rapidly internalized through the endosomal pathway, where it colocalizes with the tetraspanin CD63. In the plasma membrane, PrPc colocalizes with the tetraspanin CD81. Cross-linking with anti-PrPc or anti-CD81 causes clustering of PrPc and CD81, suggesting they can share the same microdomain. These data are consistent with a role for tetraspanin-enriched microdomains in trafficking of PrPc. These results, when taken together with recent evidence that exosomes released from cells as a result of endosomal-mediated recycling to the plasma membrane contain prion infectivity, provide a pathway for the propagation of prion diseases.

PAW35 Anti-prion protein monoclonal antibodies at low doses effectively treat prion disease in mice without side-effects

2010 ◽  
Vol 81 (11) ◽  
pp. e33-e33 ◽  
Author(s):  
C. Carswell ◽  
A. Khalili-Shirazi ◽  
S. Brandner ◽  
S. Martins ◽  
R. Drynda ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Side Effects ◽  
Prion Protein ◽  
Prion Disease ◽  
Low Doses

Influence of Calcium Ions on the Plant Cell Surface: Membrane Fusions and Conformational Changes

1974 ◽  
Vol 32 ◽  
pp. 154-155
Author(s):  
D. James Morré ◽  
Charles E. Bracker ◽  
William J. VanDerWoude
Keyword(s):  
Cell Wall ◽  
Cell Surface ◽  
Conformational Changes ◽  
Calcium Ions ◽  
Surface Membrane ◽  
Carboxyl Groups ◽  
Cross Linking ◽  
Ultrastructural Evidence ◽  
Glycine Max L ◽  
Wall Extensibility

Calcium ions in the concentration range 5-100 mM inhibit auxin-induced cell elongation and wall extensibility of plant stems. Inhibition of wall extensibility requires that the tissue be living; growth inhibition cannot be explained on the basis of cross-linking of carboxyl groups of cell wall uronides by calcium ions. In this study, ultrastructural evidence was sought for an interaction of calcium ions with some component other than the wall at the cell surface of soybean (Glycine max (L.) Merr.) hypocotyls.

Cross-Linked αsγt-Chain Hybrids in Plasma Clots Studied by 1D- and 2D Electrophoresis and Western Blotting

1993 ◽  
Vol 70 (03) ◽  
pp. 438-442 ◽  
Author(s):  
B Grøn ◽  
C Filion-Myklebust ◽  
S Bjørnsen ◽  
P Haidaris ◽  
F Brosstad
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibodies ◽  
Human Plasma ◽  
Western Blotting ◽  
Isoelectric Point ◽  
Factor Xiii ◽  
Cross Linking ◽  
2D Electrophoresis ◽  
Complex Phenomenon ◽  
Fibrinopeptide A

SummaryFibrinogen and fibrin related chains in reduced human plasma as well as the bonds interlinking partially cross-linked fibrin from plasma clots have been studied by means of 1D- and 2D electrophoresis and Western blotting. Immunovisualization of reduced plasma or partially cross-linked fibrin with monoclonal antibodies specific for the α-chains or the γ-chains have shown that several bands represent material belonging to both chains. In order to decide whether these bands constitute αγ-chain hybrids or superimposed α- and γ-chain dimers, the cross-linked material was separated according to both isoelectric point (pI) and molecular weight (MW) using Pharmacia’s Multiphor II system. Western blotting of the second dimension gels revealed that partially cross-linked fibrin contains αsγt-chain hybrids and γ- polymers, in addition to the well-known γ-dimers and α-polymers. The main αsγt-chain hybrid has a pI between that of the α- and the γ-chains, a MW of about 200 kDa and contains Aα-chains with intact fibrinopeptide A (FPA). It was also observed that soluble fibrinogen/fibrin complexes as well as partially cross-linked fibrin contain degraded α-dimers with MWs close to the γ-dimers. These findings demonstrate that factor XIII-catalyzed cross-linking of fibrin is a more complex phenomenon than earlier recognized.

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