HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 47, 32471-32483, November 21, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/47/32471    most recent M709870200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bravo, R. Articles by Fernàndez-Busquets, X. Search for Related Content PubMed PubMed Citation Articles by Bravo, R. Articles by Fernàndez-Busquets, X. Social Bookmarking                      What's this?

Sulfated Polysaccharides Promote the Assembly of Amyloid β_1–42 Peptide into Stable Fibrils of Reduced Cytotoxicity^*

Ramona Bravo, Muriel Arimon, Juan José Valle-Delgado¹, Raquel García, Núria Durany^¶, Susanna Castel, Montserrat Cruz, Salvador Ventura^||, and Xavier Fernàndez-Busquets²

From the Biomolecular Interactions Team, Nanobioengineering Group, Institute for Bioengineering of Catalonia, and Nanoscience and Nanotechnology Institute, Barcelona Science Park, University of Barcelona, Baldiri Reixac 10, Barcelona E08028, the Scientific and Technical Services, University of Barcelona, Barcelona E08028, the ^¶Facultat de Ciències de la Salut, Universitat Internacional de Catalunya, Josep Trueta s/n, Sant Cugat del Vallès E08195, and the ^||Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra E08193, Spain

The histopathological hallmarks of Alzheimer disease are the self-aggregation of the amyloid β peptide (Aβ) in extracellular amyloid fibrils and the formation of intraneuronal Tau filaments, but a convincing mechanism connecting both processes has yet to be provided. Here we show that the endogenous polysaccharide chondroitin sulfate B (CSB) promotes the formation of fibrillar structures of the 42-residue fragment, Aβ_1–42. Atomic force microscopy visualization, thioflavin T fluorescence, CD measurements, and cell viability assays indicate that CSB-induced fibrils are highly stable entities with abundant β-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for Aβ_1–42 fibrils that is consistent with the majority of available data, it is an energetically favorable assembly that minimizes the exposure of hydrophobic areas, and it explains why fibrils do not grow in thickness. Fluorescence measurements of the effect of different Aβ_1–42 species on Ca²⁺ homeostasis show that weakly structured nodular fibrils, but not CSB-induced smooth fibrils, trigger a rise in cytosolic Ca²⁺ that depends on the presence of both extracellular and intracellular stocks. In vitro assays indicate that such transient, local Ca²⁺ increases can have a direct effect in promoting the formation of Tau filaments similar to those isolated from Alzheimer disease brains.

Received for publication, December 4, 2007 , and in revised form, September 9, 2008.

^* This work was supported in part by the Generalitat de Catalunya, Spain (Grant 2005-SGR00037) and the Ministerio de Ciencia e Innovación (MCI), Spain (Grants BIO2002-00128, BIO2005-01591, and CSD2006-00012), which included Fondo Europeo de Desarrollo Regional funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Juan de la Cierva Programme (MCI).

² To whom correspondence should be addressed. Tel.: 34-93-403-7180; Fax: 34-93-403-7181; E-mail: xfernandez_busquets{at}ub.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?