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

Abstract

The histopathological hallmarks of Alzheimer disease are the self-aggregation of the amyloid beta peptide (Abeta) 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, Abeta(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 beta-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for Abeta(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 Abeta(1-42) species on Ca(2+) homeostasis show that weakly structured nodular fibrils, but not CSB-induced smooth fibrils, trigger a rise in cytosolic Ca(2+) that depends on the presence of both extracellular and intracellular stocks. In vitro assays indicate that such transient, local Ca(2+) increases can have a direct effect in promoting the formation of Tau filaments similar to those isolated from Alzheimer disease brains.

• Authors: Ramona Bravo, Muriel Arimon, Juan José Valle-Delgado, Raquel García, Núria Durany, Susanna Castel, Montserrat Cruz, Salvador Ventura, Xavier Fernàndez-Busquets
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 47 Pg. 32471-83 (Nov 21 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18819917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Benzothiazoles
• Peptide Fragments
• Peptides
• Polysaccharides
• Thiazoles
• amyloid beta-protein (1-42)
• tau Proteins
• thioflavin T
• Calcium

Topics

• Amyloid beta-Peptides (chemistry, metabolism)
• Benzothiazoles
• Calcium (metabolism)
• Cell Line, Tumor
• Cell Survival
• Circular Dichroism
• Cytosol (metabolism)
• Humans
• Microscopy, Atomic Force
• Peptide Fragments (chemistry, metabolism)
• Peptides (chemistry)
• Polysaccharides (chemistry)
• Protein Binding
• Protein Conformation
• Protein Structure, Secondary
• Thiazoles (chemistry)
• tau Proteins (chemistry)