Human Anti-prion Antibodies Block Prion Peptide Fibril Formation and Neurotoxicity

Abstract

Prion diseases are a group of rare, fatal neurodegenerative disorders associated with a conformational transformation of the cellular prion protein (PrPC) into a self-replicating and proteinase K-resistant conformer, termed scrapie PrP (PrPSc). Aggregates of PrPSc deposited around neurons lead to neuropathological alterations. Currently, there is no effective treatment for these fatal illnesses; thus, the development of an effective therapy is a priority. PrP peptide-based ELISA assay methods were developed for detection and immunoaffinity chromatography capture was developed for purification of naturally occurring PrP peptide autoantibodies present in human CSF, individual donor serum, and commercial preparations of pooled intravenous immunoglobulin (IVIg). The ratio of anti-PrP autoantibodies (PrP-AA) to total IgG was ∼1:1200. The binding epitope of purified PrP-AA was mapped to an N-terminal region comprising the PrP amino acid sequence KTNMK. Purified PrP-AA potently blocked fibril formation by a toxic 21-amino acid fragment of the PrP peptide containing the amino acid alanine to valine substitution corresponding to position 117 of the full-length peptide (A117V). Furthermore, PrP-AA attenuated the neurotoxicity of PrP(A117V) and wild-type peptides in rat cerebellar granule neuron (CGN) cultures. In contrast, IgG preparations depleted of PrP-AA had little effect on PrP fibril formation or PrP neurotoxicity. The specificity of PrP-AA was demonstrated by immunoprecipitating PrP protein in brain tissues of transgenic mice expressing the human PrP(A117V) epitope and Sc237 hamster. Based on these intriguing findings, it is suggested that human PrP-AA may be useful for interfering with the pathogenic effects of pathogenic prion proteins and, thereby has the potential to be an effective means for preventing or attenuating human prion disease progression. Prion diseases are a group of rare, fatal neurodegenerative disorders associated with a conformational transformation of the cellular prion protein (PrPC) into a self-replicating and proteinase K-resistant conformer, termed scrapie PrP (PrPSc). Aggregates of PrPSc deposited around neurons lead to neuropathological alterations. Currently, there is no effective treatment for these fatal illnesses; thus, the development of an effective therapy is a priority. PrP peptide-based ELISA assay methods were developed for detection and immunoaffinity chromatography capture was developed for purification of naturally occurring PrP peptide autoantibodies present in human CSF, individual donor serum, and commercial preparations of pooled intravenous immunoglobulin (IVIg). The ratio of anti-PrP autoantibodies (PrP-AA) to total IgG was ∼1:1200. The binding epitope of purified PrP-AA was mapped to an N-terminal region comprising the PrP amino acid sequence KTNMK. Purified PrP-AA potently blocked fibril formation by a toxic 21-amino acid fragment of the PrP peptide containing the amino acid alanine to valine substitution corresponding to position 117 of the full-length peptide (A117V). Furthermore, PrP-AA attenuated the neurotoxicity of PrP(A117V) and wild-type peptides in rat cerebellar granule neuron (CGN) cultures. In contrast, IgG preparations depleted of PrP-AA had little effect on PrP fibril formation or PrP neurotoxicity. The specificity of PrP-AA was demonstrated by immunoprecipitating PrP protein in brain tissues of transgenic mice expressing the human PrP(A117V) epitope and Sc237 hamster. Based on these intriguing findings, it is suggested that human PrP-AA may be useful for interfering with the pathogenic effects of pathogenic prion proteins and, thereby has the potential to be an effective means for preventing or attenuating human prion disease progression. IntroductionPrion diseases, or transmissible spongiform encephalopathies (TSEs), 2The abbreviations used are: TSEtransmissible spongiform encephalopathiesPrPprion proteinCJDCreutzfeldt-Jakob diseaseADAlzheimer diseaseIVIgintravenous immunoglobulinPrP-AAanti-PrP autoantibodiesCGNcerebellar granule neuronAβbeta amyloid. are rapidly progressive neurodegenerative disorders with untreatable invariably fatal outcomes. Disease caused by altered forms of prion protein (PrP) include scrapie in sheep, bovine spongiform encephalopathy in cattle, as well as the human forms Kuru, Creutzfeldt-Jakob disease (CJD and vCJD), and the Gerstmann-Straussler-Scheinker (GSS) syndrome (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar). These diseases are most likely caused by misfolding and aggregation of the normal host protein (PrPC) into a highly insoluble form PrPSc. In this process, a portion of the α-helix and random coil structure of PrPC, which is ubiquitously expressed in neurons and leukocytes, adopts the PrPSc β-pleated conformation, rendering the protein poorly soluble in water and resistant to protease digestion (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar). Autopsy on the brains of prion disease patients has identified amyloid plaques comprised of insoluble PrPSc aggregates deposited around neurons in affected brain regions, which is thought to induce neuronal dysfunction and death, thus producing the clinical symptoms of infection (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar, 2Bugiani O. Giaccone G. Piccardo P. Morbin M. Tagliavini F. Ghetti B. Neuropathology of Gerstmann-Sträussler-Scheinker disease.Microsc. Res. Tech. 2000; 50: 10-15Crossref PubMed Scopus (45) Google Scholar, 3Ghetti B. Piccardo P. Frangione B. Bugiani O. Giaccone G. Young K. Prelli F. Farlow M.R. Dlouhy S.R. Tagliavini F. Prion protein amyloidosis.Brain Pathol. 1996; 6: 127-145Crossref PubMed Scopus (171) Google Scholar, 4Giaccone G. Verga L. Bugiani O. Frangione B. Serban D. Prusiner S.B. Farlow M.R. Ghetti B. Tagliavini F. Prion protein preamyloid and amyloid deposits in Gerstmann-Sträussler-Scheinker disease, Indiana kindred.Proc. Natl. Acad. Sci. U.S.A. 1992; 89: 9349-9353Crossref PubMed Scopus (84) Google Scholar, 5Kitamoto T. Tateishi J. Tashima T. Takeshita I. Barry R.A. DeArmond S.J. Prusiner S.B. Amyloid plaques in Creutzfeldt-Jakob disease stain with prion protein antibodies.Ann. Neurol. 1986; 20: 204-208Crossref PubMed Scopus (131) Google Scholar, 6Tateishi J. Kitamoto T. Hashiguchi H. Shii H. Gerstmann-Sträussler-Scheinker disease: immunohistological and experimental studies.Ann. Neurol. 1988; 24: 35-40Crossref PubMed Scopus (46) Google Scholar, 7Ghetti B. Tagliavini F. Masters C.L. Beyreuther K. Giaccone G. Verga L. Farlow M.R. Conneally P.M. Dlouhy S.R. Azzarelli B. Gerstmann-Sträussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family.Neurology. 1989; 39: 1453-1461Crossref PubMed Google Scholar). The primacy of a single protein causing disease across species by diverse mechanisms is unique in biology.To date, there are no therapeutic treatments available for prion diseases. However, recent studies in cultured cells and mice indicate that immunotherapeutic strategies employing antibodies against the cellular form of PrPC can antagonize prion infectivity and disease development. Monoclonal antibodies (mAbs) or recombinant F(ab) fragments recognizing PrP effectively prevented prion infection of susceptible mouse neuroblastoma cells and abrogated de novo PrPSc formation in chronically infected cells (8Peretz D. Williamson R.A. Kaneko K. Vergara J. Leclerc E. Schmitt-Ulms G. Mehlhorn I.R. Legname G. Wormald M.R. Rudd P.M. Dwek R.A. Burton D.R. Prusiner S.B. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity.Nature. 2001; 412: 739-743Crossref PubMed Scopus (468) Google Scholar, 9Enari M. Flechsig E. Weissmann C. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 9295-9299Crossref PubMed Scopus (376) Google Scholar). In addition, passive transfer of a PrP mAb into scrapie-infected mice suppressed peripheral prion replication and infectivity, and significantly delayed onset of the disease (10Heppner F.L. Musahl C. Arrighi I. Klein M.A. Rülicke T. Oesch B. Zinkernagel R.M. Kalinke U. Aguzzi A. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies.Science. 2001; 294: 178-182Crossref PubMed Scopus (310) Google Scholar, 11White A.R. Enever P. Tayebi M. J. D. J. Monoclonal antibodies inhibit prion replication and the development of prion PubMed Scopus Google Scholar, D.R. M. Frangione B. T. the onset of prion disease in J. Pathol. PubMed Scopus (171) Google Scholar). no effects were in these These that immunotherapeutic strategies for human prion diseases are and H. K. B. K. F. Farlow M. of amyloid in 2001; PubMed Scopus Google Scholar, L. P. with disease of peptide antibodies PubMed Scopus Google suggested that an or to antibodies for amyloid peptides may be to disease immunoglobulin preparations containing of antibodies or purified autoantibodies against effects in with patients H. K. B. K. F. Farlow M. of amyloid in 2001; PubMed Scopus Google Scholar, H. C. F. K. C. B. Farlow M. antibodies against amyloid a potential treatment for Neurol. PubMed Scopus Google Scholar, C. H. L. A. U. S.J. A. C. Farlow M. containing antibodies against for the treatment of Neurol. PubMed Scopus (310) Google Scholar, F. C. M. PubMed Scopus Google Scholar). demonstrated that these autoantibodies or fibril formation and toxic effects in neurons H. F. L. Farlow M. antibodies fibril formation and PubMed Scopus Google the pathogenic mechanisms of and prion diseases toxic conformational and of insoluble protein aggregates (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar, M. and prion J. PubMed Scopus Google Scholar, S.J. A. A. D. Prusiner S.B. scrapie prion accumulation of the prion protein scrapie Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, T. M. 2001; PubMed Google Scholar, T. for prion and J. PubMed Scopus Google Scholar, P. PubMed Scopus Google and the with autoantibodies for treatment of that anti-PrP autoantibodies (PrP-AA) may be present in The potential for of PrP-AA is on the of mouse to fibril and inhibit the effect of PrPSc E. O. M. B. of the human prion peptide Res. 2001; PubMed Scopus Google Scholar). of purified human PrP-AA mouse is a potential for host to mouse in the peptide fragment human PrP of the to form and to in brains L. E. T. L. M. G. The neurotoxicity of prion protein (PrP) peptide is of the expression of PrP and is by PrP PubMed Scopus Google Scholar, F. G. P. Bugiani O. M. on peptide fragments of prion 2001; PubMed Scopus Google Scholar). peptide has used in an in to neurotoxicity G. E. M. Bugiani O. Tagliavini F. of a prion protein PubMed Scopus Google Scholar, G. E. M. M. Verga L. prion protein fragment rat and J. 6: PubMed Scopus Google Scholar, D.R. J. cells cellular PrP in with a PrP PubMed Scopus Google Scholar, D.R. B. prion protein fragment of in 1996; PubMed Scopus Google Scholar, D.R. B. of and host prion protein in neurotoxicity of a prion protein 1996; PubMed Scopus Google Scholar, D.R. Prion cells altered to a prion protein Res. PubMed Scopus Google Scholar). in the prion protein to a substitution of valine for alanine peptide position 117 is associated with an prion disease DeArmond Prusiner S.B. Prion disease with of PubMed Scopus Google Scholar, J. prion and Google Scholar, C. T. E. H. Prusiner S.B. prion protein in a with the form of Gerstmann-Sträussler-Scheinker 1991; PubMed Scopus Google that is by amyloid plaques in the and D.R. of the prion protein peptide the J. 2000; PubMed Scopus Google Scholar). The the The that a of the toxic in that there may be in the of neurotoxicity of PrPSc. The the effects of The is to that of which the of and neuronal PrPC the is of neuronal PrPC expression or of D.R. of the prion protein peptide the J. 2000; PubMed Scopus Google this that PrP-AA are present in human and These autoantibodies be purified by chromatography with identified a amino acid binding epitope for Furthermore, demonstrated that purified PrP-AA effectively cultured granule neurons (CGN) against and PrP-AA in human and normal by developed and used an with the human PrP sequence which is termed to human PrP-AA or individual was with capture of in an ELISA assay PrP-AA The was depleted of antibodies which In contrast, purified PrP-AA be by ELISA with the peptide specificity of PrP-AA was by immunoprecipitating PrP(A117V) of brains transgenic mice that the human was by a containing the which has used to M.R. P. M. DeArmond S.J. Prusiner S.B. form of the prion protein in neurodegenerative PubMed Scopus Google Scholar). has that PrP a human single PrP M. A. M. of human antibodies recognizing a prion protein epitope expressed on the of human PubMed Scopus Google that brains expressing the region of the protein to human PrP the expression of PrP(A117V) in transgenic mouse brain the available mouse a protein of the in brain transgenic PrP or mice of proteins brain of PrP(A117V) transgenic mice was with purified no protein with of brains of PrP(A117V) or mice demonstrated a corresponding to PrP in the and of the transgenic mice protein species were detection of PrP-AA with the PrP(A117V) was by the protein these indicate that PrP-AA PrP(A117V) with specificity and to PrP-AA to PrPSc brain a Sc237 with or were by PrP-AA or autoantibodies against as a demonstrated that purified PrP-AA PrP and PrPSc of PrP-AA specificity for transgenic wild-type were to the PrP which was in brain the of PrP(A117V) in brain of transgenic mice by with purified PrP-AA or were to with purified PrP-AA the PrP protein in of brain and cerebellar of transgenic mice were with the to the of PrP in PrP(A117V) transgenic of brain transgenic mouse and Sc237 with or proteinase PrP-AA or autoantibodies against anti-PrP which mouse and was used for to indicate of were in Purified PrP-AA PrP and PrPSc against PrP PrPSc The was a single that was with IgG depleted of autoantibodies against of PrP-AA in was to be a total IgG of The of IgG in the purified PrP-AA were as and the IgG of purified PrP-AA are to the of IgG in and human Furthermore, the PrP-AA binding epitope was an a of peptides and of PrP-AA the of and a as demonstrated in and D. in this are for binding substitution or of PrP-AA binding PrP-AA binding of PrP-AA were a peptide of amino or single amino peptides region which were and on are in and C. were with PrP-AA and were The sequence to be highly peptide is by as in B. in which binding are the are for by and a that to purified human PrP-AA PrP fibril formation as well as and studies that or peptide with purified human PrP-AA prevented fibril formation and fibril in a as by a in and with the These were in of PrP-AA and and of PrP-AA on PrP fibril of fibril formation and PrP-AA of fibril formation and PrP-AA of peptides with or purified PrP-AA in Purified PrP-AA significantly fibril of peptides with purified PrP-AA or IgG in for Purified PrP-AA significantly as by were in and as the with PrP of the with or PrP-AA were to and F. of the are in and IgG depleted of the assay and to of with PrP by and were by and by The of PrP with or PrP-AA that PrP-AA treatments significantly the PrP that PrP-AA blocked PrP fibril of these the and PrP-AA cultured rat neurons of as by to The of was to form neuronal in a In contrast, a peptide with a sequence no neurotoxicity with These the to of which had to form of PrP peptides on of fibril neurotoxicity was in The neurons were to of to or and peptide for was by neurons with are expressed as of The the of a single which has with by of PrP-AA in the The PrP-AA prevented neurotoxicity in a Purified PrP-AA significantly blocked neuronal in the were with fibril and fibril that had with PrP-AA for was by neurons with are expressed as of The the of a single which has with by IgG depleted of neurotoxicity of or be blocked by with purified PrP-AA to cultures of PrP-AA prevented neurotoxicity of the as or In addition, PrP-AA potently blocked wild-type neurotoxicity of to against neurotoxicity by of PrP-AA on or neurotoxicity. of rat to or fibril in a of neuronal a Purified PrP-AA significantly attenuated neuronal peptides were with PrP-AA to were with PrP-AA to wild-type were with PrP-AA to was by neurons with The the of a with with or IgG depleted of studies the wild-type induce neurotoxicity D.R. of the prion protein peptide the J. 2000; PubMed Scopus Google Scholar). that purified human PrP-AA against neurotoxicity of of with with the treatment of these cultures with to with treatment of was with PrP-AA of In contrast, demonstrated no identified prion antibodies in and normal and demonstrated of PrP in cerebellar is the and of PrP antibodies with no exposure to prion and that PrP-AA to the PrP and PrPSc. that these autoantibodies may normal of PrP replication or to for antibodies H. K. B. K. F. Farlow M. of amyloid in 2001; PubMed Scopus Google Scholar, H. C. F. K. C. B. Farlow M. antibodies against amyloid a potential treatment for Neurol. PubMed Scopus Google Scholar). that human PrP-AA can be thus, the potential for producing a to in the is has suggested that PrP antibodies may be an effective for prion diseases C. F. I. Klein M.A. Aguzzi A. and the B. Sci. 2001; PubMed Scopus Google Scholar). is a disease, PrPSc in tissues PrPSc an for therapeutic the of peripheral tissues with which significantly of the antibodies the brain are with a PrP or passive with of an therapy may be prion a and there likely be to or the infectivity of this peptide C. F. I. Klein M.A. Aguzzi A. and the B. Sci. 2001; PubMed Scopus Google Scholar). In addition, a clinical in patients with the to on the may a the of present of of PrP-AA in normal human and pooled which can be purified and a for rapidly an effective and for prion diseases. a the PrP epitope be developed on the binding sequence of antibodies may be as purified antibodies the of of there is that with antibodies may to the mouse that purified PrP-AA inhibit PrP fibril formation and PrP as in studies mouse PrP antibodies (8Peretz D. Williamson R.A. Kaneko K. Vergara J. Leclerc E. Schmitt-Ulms G. Mehlhorn I.R. Legname G. Wormald M.R. Rudd P.M. Dwek R.A. Burton D.R. Prusiner S.B. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity.Nature. 2001; 412: 739-743Crossref PubMed Scopus (468) Google Scholar, 9Enari M. Flechsig E. Weissmann C. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 9295-9299Crossref PubMed Scopus (376) Google Scholar). The epitope for human PrP-AA is a the human acid sequence the of the which is and PrP-AA the full-length prion protein containing the expressed in a transgenic mouse human PrP-AA and to a well PrPSc human may be in to prion a The that PrP-AA binding is by a of amino that the of purified IgG is comprised of a of Furthermore, it a region the full-length peptide that is for fibril formation and neurotoxicity. binding a region of the PrP protein this purified PrP-AA be effective for treatment of prion diseases. demonstrated of and fibril formation and neurotoxicity. In addition, the of neuronal by these peptides that PrP-AA may a to prion diseases PrP-AA with it is to a to the human PrP-AA can with human PrPSc and neurotoxicity in the it is in studies to the effect of the PrP-AA on aggregation of full-length PrP or the N-terminal of wild-type are in transgenic expressing forms of the full-length protein to this that PrP-AA is in normal human and and can be purified pooled The of PrP-AA to antibodies treatment of prion diseases with PrP-AA is highly clinical for are and demonstrated P. B. T. C. L. of intravenous immunoglobulin for treatment of PubMed Scopus Google Scholar). of purified human PrP-AA or may be used to or prion disease progression. IntroductionPrion diseases, or transmissible spongiform encephalopathies (TSEs), 2The abbreviations used are: TSEtransmissible spongiform encephalopathiesPrPprion proteinCJDCreutzfeldt-Jakob diseaseADAlzheimer diseaseIVIgintravenous immunoglobulinPrP-AAanti-PrP autoantibodiesCGNcerebellar granule neuronAβbeta amyloid. are rapidly progressive neurodegenerative disorders with untreatable invariably fatal outcomes. Disease caused by altered forms of prion protein (PrP) include scrapie in sheep, bovine spongiform encephalopathy in cattle, as well as the human forms Kuru, Creutzfeldt-Jakob disease (CJD and vCJD), and the Gerstmann-Straussler-Scheinker (GSS) syndrome (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar). These diseases are most likely caused by misfolding and aggregation of the normal host protein (PrPC) into a highly insoluble form PrPSc. In this process, a portion of the α-helix and random coil structure of PrPC, which is ubiquitously expressed in neurons and leukocytes, adopts the PrPSc β-pleated conformation, rendering the protein poorly soluble in water and resistant to protease digestion (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar). Autopsy on the brains of prion disease patients has identified amyloid plaques comprised of insoluble PrPSc aggregates deposited around neurons in affected brain regions, which is thought to induce neuronal dysfunction and death, thus producing the clinical symptoms of infection (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar, 2Bugiani O. Giaccone G. Piccardo P. Morbin M. Tagliavini F. Ghetti B. Neuropathology of Gerstmann-Sträussler-Scheinker disease.Microsc. Res. Tech. 2000; 50: 10-15Crossref PubMed Scopus (45) Google Scholar, 3Ghetti B. Piccardo P. Frangione B. Bugiani O. Giaccone G. Young K. Prelli F. Farlow M.R. Dlouhy S.R. Tagliavini F. Prion protein amyloidosis.Brain Pathol. 1996; 6: 127-145Crossref PubMed Scopus (171) Google Scholar, 4Giaccone G. Verga L. Bugiani O. Frangione B. Serban D. Prusiner S.B. Farlow M.R. Ghetti B. Tagliavini F. Prion protein preamyloid and amyloid deposits in Gerstmann-Sträussler-Scheinker disease, Indiana kindred.Proc. Natl. Acad. Sci. U.S.A. 1992; 89: 9349-9353Crossref PubMed Scopus (84) Google Scholar, 5Kitamoto T. Tateishi J. Tashima T. Takeshita I. Barry R.A. DeArmond S.J. Prusiner S.B. Amyloid plaques in Creutzfeldt-Jakob disease stain with prion protein antibodies.Ann. Neurol. 1986; 20: 204-208Crossref PubMed Scopus (131) Google Scholar, 6Tateishi J. Kitamoto T. Hashiguchi H. Shii H. Gerstmann-Sträussler-Scheinker disease: immunohistological and experimental studies.Ann. Neurol. 1988; 24: 35-40Crossref PubMed Scopus (46) Google Scholar, 7Ghetti B. Tagliavini F. Masters C.L. Beyreuther K. Giaccone G. Verga L. Farlow M.R. Conneally P.M. Dlouhy S.R. Azzarelli B. Gerstmann-Sträussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family.Neurology. 1989; 39: 1453-1461Crossref PubMed Google Scholar). The primacy of a single protein causing disease across species by diverse mechanisms is unique in biology.To date, there are no therapeutic treatments available for prion diseases. However, recent studies in cultured cells and mice indicate that immunotherapeutic strategies employing antibodies against the cellular form of PrPC can antagonize prion infectivity and disease development. Monoclonal antibodies (mAbs) or recombinant F(ab) fragments recognizing PrP effectively prevented prion infection of susceptible mouse neuroblastoma cells and abrogated de novo PrPSc formation in chronically infected cells (8Peretz D. Williamson R.A. Kaneko K. Vergara J. Leclerc E. Schmitt-Ulms G. Mehlhorn I.R. Legname G. Wormald M.R. Rudd P.M. Dwek R.A. Burton D.R. Prusiner S.B. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity.Nature. 2001; 412: 739-743Crossref PubMed Scopus (468) Google Scholar, 9Enari M. Flechsig E. Weissmann C. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody.Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 9295-9299Crossref PubMed Scopus (376) Google Scholar). In addition, passive transfer of a PrP mAb into scrapie-infected mice suppressed peripheral prion replication and infectivity, and significantly delayed onset of the disease (10Heppner F.L. Musahl C. Arrighi I. Klein M.A. Rülicke T. Oesch B. Zinkernagel R.M. Kalinke U. Aguzzi A. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies.Science. 2001; 294: 178-182Crossref PubMed Scopus (310) Google Scholar, 11White A.R. Enever P. Tayebi M. J. D. J. Monoclonal antibodies inhibit prion replication and the development of prion PubMed Scopus Google Scholar, D.R. M. Frangione B. T. the onset of prion disease in J. Pathol. PubMed Scopus (171) Google Scholar). no effects were in these These that immunotherapeutic strategies for human prion diseases are and H. K. B. K. F. Farlow M. of amyloid in 2001; PubMed Scopus Google Scholar, L. P. with disease of peptide antibodies PubMed Scopus Google suggested that an or to antibodies for amyloid peptides may be to disease immunoglobulin preparations containing of antibodies or purified autoantibodies against effects in with patients H. K. B. K. F. Farlow M. of amyloid in 2001; PubMed Scopus Google Scholar, H. C. F. K. C. B. Farlow M. antibodies against amyloid a potential treatment for Neurol. PubMed Scopus Google Scholar, C. H. L. A. U. S.J. A. C. Farlow M. containing antibodies against for the treatment of Neurol. PubMed Scopus (310) Google Scholar, F. C. M. PubMed Scopus Google Scholar). demonstrated that these autoantibodies or fibril formation and toxic effects in neurons H. F. L. Farlow M. antibodies fibril formation and PubMed Scopus Google the pathogenic mechanisms of and prion diseases toxic conformational and of insoluble protein aggregates (1Prusiner S.B. Molecular biology of prion diseases.Science. 1991; 252: 1515-1522Crossref PubMed Scopus (1737) Google Scholar, M. and prion J. PubMed Scopus Google Scholar, S.J. A. A. D. Prusiner S.B. scrapie prion accumulation of the prion protein scrapie Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, T. M. 2001; PubMed Google Scholar, T. for prion and J. PubMed Scopus Google Scholar, P. PubMed Scopus Google and the with autoantibodies for treatment of that anti-PrP autoantibodies (PrP-AA) may be present in The potential for of PrP-AA is on the of mouse to fibril and inhibit the effect of PrPSc E. O. M. B. of the human prion peptide Res. 2001; PubMed Scopus Google Scholar). of purified human PrP-AA mouse is a potential for host to mouse in the peptide fragment human PrP of the to form and to in brains L. E. T. L. M. G. The neurotoxicity of prion protein (PrP) peptide is of the expression of PrP and is by PrP PubMed Scopus Google Scholar, F. G. P. Bugiani O. M. on peptide fragments of prion 2001; PubMed Scopus Google Scholar). peptide has used in an in to neurotoxicity G. E. M. Bugiani O. Tagliavini F. of a prion protein PubMed Scopus Google Scholar, G. E. M. M. Verga L. prion protein fragment rat and J. 6: PubMed Scopus Google Scholar, D.R. J. cells cellular PrP in with a PrP PubMed Scopus Google Scholar, D.R. B. prion protein fragment of in 1996; PubMed Scopus Google Scholar, D.R. B. of and host prion protein in neurotoxicity of a prion protein 1996; PubMed Scopus Google Scholar, D.R. Prion cells altered to a prion protein Res. PubMed Scopus Google Scholar). in the prion protein to a substitution of valine for alanine peptide position 117 is associated with an prion disease DeArmond Prusiner S.B. Prion disease with of PubMed Scopus Google Scholar, J. prion and Google Scholar, C. T. E. H. Prusiner S.B. prion protein in a with the form of Gerstmann-Sträussler-Scheinker 1991; PubMed Scopus Google that is by amyloid plaques in the and D.R. of the prion protein peptide the J. 2000; PubMed Scopus Google Scholar). The the The that a of the toxic in that there may be in the of neurotoxicity of PrPSc. The the effects of The is to that of which the of and neuronal PrPC the is of neuronal PrPC expression or of D.R. of the prion protein peptide the J. 2000; PubMed Scopus Google this that PrP-AA are present in human and These autoantibodies be purified by chromatography with identified a amino acid binding epitope for Furthermore, demonstrated that purified PrP-AA effectively cultured granule neurons (CGN) against and neurotoxicity.