Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.

<h4>Background</h4>Alzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-β peptide (Aβ). The correlation between clinical symptoms of AD and Aβ depositions is, however, weak. Instead small and soluble Aβ oligomers are suggested to exert the major p...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Malin Lindhagen-Persson, Kristoffer Brännström, Monika Vestling, Michael Steinitz, Anders Olofsson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fcc89ff6418c4b12b97c6f4e5c066d44
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:fcc89ff6418c4b12b97c6f4e5c066d44
record_format	dspace
spelling	oai:doaj.org-article:fcc89ff6418c4b12b97c6f4e5c066d442021-11-18T07:37:00ZAmyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.1932-620310.1371/journal.pone.0013928https://doaj.org/article/fcc89ff6418c4b12b97c6f4e5c066d442010-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21085663/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Alzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-β peptide (Aβ). The correlation between clinical symptoms of AD and Aβ depositions is, however, weak. Instead small and soluble Aβ oligomers are suggested to exert the major pathological effects. In strong support of this notion, immunological targeting of Aβ oligomers in AD mice-models shows that memory impairments can be restored without affecting the total burden of Aβ deposits. Consequently a specific immunological targeting of Aβ oligomers is of high therapeutic interest.<h4>Methodology/principal findings</h4>Previously the generation of conformational-dependent oligomer specific anti-Aβ antibodies has been described. However, to avoid the difficult task of identifying a molecular architecture only present on oligomers, we have focused on a more general approach based on the hypothesis that all oligomers expose multiple identical epitopes and therefore would have an increased binding to a multivalent receptor. Using the polyvalent IgM immunoglobulin we have developed a monoclonal anti-Aβ antibody (OMAB). OMAB only demonstrates a weak interaction with Aβ monomers and dimers having fast on and off-rate kinetics. However, as an effect of avidity, its interaction with Aβ-oligomers results in a strong complex with an exceptionally slow off-rate. Through this mechanism a selectivity towards Aβ oligomers is acquired and OMAB fully inhibits the cytotoxic effect exerted by Aβ(1-42) at highly substoichiometric ratios. Anti-Aβ auto-antibodies of IgM isotype are frequently present in the sera of humans. Through a screen of endogenous anti-Aβ IgM auto-antibodies from a group of healthy individuals we show that all displays a preference for oligomeric Aβ.<h4>Conclusions/significance</h4>Taken together we provide a simple and general mechanism for targeting of oligomers without the requirement of conformational-dependent epitopes. In addition, our results suggest that IgM anti-Aβ auto-antibodies may exert a more specific protective mechanism in vivo than previously anticipated.Malin Lindhagen-PerssonKristoffer BrännströmMonika VestlingMichael SteinitzAnders OlofssonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 11, p e13928 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Malin Lindhagen-Persson Kristoffer Brännström Monika Vestling Michael Steinitz Anders Olofsson Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.
description	<h4>Background</h4>Alzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-β peptide (Aβ). The correlation between clinical symptoms of AD and Aβ depositions is, however, weak. Instead small and soluble Aβ oligomers are suggested to exert the major pathological effects. In strong support of this notion, immunological targeting of Aβ oligomers in AD mice-models shows that memory impairments can be restored without affecting the total burden of Aβ deposits. Consequently a specific immunological targeting of Aβ oligomers is of high therapeutic interest.<h4>Methodology/principal findings</h4>Previously the generation of conformational-dependent oligomer specific anti-Aβ antibodies has been described. However, to avoid the difficult task of identifying a molecular architecture only present on oligomers, we have focused on a more general approach based on the hypothesis that all oligomers expose multiple identical epitopes and therefore would have an increased binding to a multivalent receptor. Using the polyvalent IgM immunoglobulin we have developed a monoclonal anti-Aβ antibody (OMAB). OMAB only demonstrates a weak interaction with Aβ monomers and dimers having fast on and off-rate kinetics. However, as an effect of avidity, its interaction with Aβ-oligomers results in a strong complex with an exceptionally slow off-rate. Through this mechanism a selectivity towards Aβ oligomers is acquired and OMAB fully inhibits the cytotoxic effect exerted by Aβ(1-42) at highly substoichiometric ratios. Anti-Aβ auto-antibodies of IgM isotype are frequently present in the sera of humans. Through a screen of endogenous anti-Aβ IgM auto-antibodies from a group of healthy individuals we show that all displays a preference for oligomeric Aβ.<h4>Conclusions/significance</h4>Taken together we provide a simple and general mechanism for targeting of oligomers without the requirement of conformational-dependent epitopes. In addition, our results suggest that IgM anti-Aβ auto-antibodies may exert a more specific protective mechanism in vivo than previously anticipated.
format	article
author	Malin Lindhagen-Persson Kristoffer Brännström Monika Vestling Michael Steinitz Anders Olofsson
author_facet	Malin Lindhagen-Persson Kristoffer Brännström Monika Vestling Michael Steinitz Anders Olofsson
author_sort	Malin Lindhagen-Persson
title	Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.
title_short	Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.
title_full	Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.
title_fullStr	Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.
title_full_unstemmed	Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.
title_sort	amyloid-β oligomer specificity mediated by the igm isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/fcc89ff6418c4b12b97c6f4e5c066d44
work_keys_str_mv	AT malinlindhagenpersson amyloidboligomerspecificitymediatedbytheigmisotypeimplicationsforaspecificprotectivemechanismexertedbyendogenousautoantibodies AT kristofferbrannstrom amyloidboligomerspecificitymediatedbytheigmisotypeimplicationsforaspecificprotectivemechanismexertedbyendogenousautoantibodies AT monikavestling amyloidboligomerspecificitymediatedbytheigmisotypeimplicationsforaspecificprotectivemechanismexertedbyendogenousautoantibodies AT michaelsteinitz amyloidboligomerspecificitymediatedbytheigmisotypeimplicationsforaspecificprotectivemechanismexertedbyendogenousautoantibodies AT andersolofsson amyloidboligomerspecificitymediatedbytheigmisotypeimplicationsforaspecificprotectivemechanismexertedbyendogenousautoantibodies
_version_	1718423200288735232

Amyloid-β oligomer specificity mediated by the IgM isotype--implications for a specific protective mechanism exerted by endogenous auto-antibodies.

Ejemplares similares