Sulfated polysaccharides promote the assembly of amyloid beta 1-42 peptide into stable fibrils of reduced cytotoxicity.
 

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09-30-08 08:55 AM
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Sulfated polysaccharides promote the assembly of amyloid beta 1-42 peptide into stable fibrils of reduced cytotoxicity.
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Sulfated polysaccharides promote the assembly of amyloid beta 1-42 peptide into stable fibrils of reduced cytotoxicity.

J Biol Chem. 2008 Sep 25;

Authors: Bravo R, Arimon M, Valle-Delgado JJ, García R, Durany N, Castel S, Cruz M, Ventura S, Fernàndez-Busquets X

The histopathological hallmarks of Alzheimer's disease (AD) are the self-aggregation of the amyloid ss peptide (Ass) 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, Ass1-42. Atomic force microscopy visualization, thioflavin T fluorescence, circular dichroism measurements, and cell viability assays indicate that CSB-induced fibrils are highly stable entities with abundant ss-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for Ass1-42 fibrils that is consistent with the majority of available data, it is an energetically favourable 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 Ass1-42 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 AD brains.

PMID: 18819917 [PubMed - as supplied by publisher]