Sulfated polysaccharides promote the assembly of amyloid beta(1-42) peptide into stable fibrils of reduced cytotoxicity.
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.
Bravo
Ramona
R
Biomolecular Interactions Team, Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona Science Park, University of Barcelona, Baldiri Reixac 10, Barcelona E08028, Spain.
Arimon
Muriel
M
Valle-Delgado
Juan José
JJ
García
Raquel
R
Durany
Núria
N
Castel
Susanna
S
Cruz
Montserrat
M
Ventura
Salvador
S
Fernàndez-Busquets
Xavier
X
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002942:Circular Dichroism; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013844:Thiazoles / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D010455:Peptides; D011134:Polysaccharides; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C009462:thioflavin T; D002118:Calcium