Sulfated polysaccharides promote the assembly of amyloid β<inf>1-42</inf> peptide into stable fibrils of reduced cytotoxicity

Ramona Bravo, Muriel Arimon, Juan José Valle-Delgado, Raquel García, Núria Durany, Susanna Castel, Montserrat Cruz, Salvador Ventura, Xavier Fernàndez-Busquets

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64 Citations (Scopus)

Abstract

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, Aβ1-42. 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 Aβ1-42 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 Aβ1-42 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. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
Original languageEnglish
Pages (from-to)32471-32483
JournalJournal of Biological Chemistry
Volume283
DOIs
Publication statusPublished - 21 Nov 2008

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