A sulfated proteoglycan aggregation factor mediates amyloid-beta peptide fibril formation and neurotoxicity.
Proteoglycans are associated with senile plaques in Alzheimer's disease and may be involved in A beta fibril formation and plaque formation. In vitro, glycosaminoglycans have been shown to inhibit the proteolysis of A beta fibrils, accelerate formation and maintain their stability. To model their interaction, we investigated the binding of a sulfated proteoglycan derived from a natural source; marine sponge Microciona prolifera aggregation factor (MAF). This species-specific re-aggregation of sponge cells has two functional properties, a Ca2+ independent cell binding activity and a Ca2+ dependent self-aggregation. It has been shown that a novel sulfated disaccharide and a pyruvylated trisaccharide are important in the Ca(2+)-dependent MAF aggregation. Aggregation demonstrated by homophilic binding of MAF subunits may be chemically distinct from other heterotypic binding effects. We investigated A beta-MAF interactions and show that MAF induces a structural transition in A beta 40 and A beta 42 from random to beta-structure as detected by circular dichroism spectroscopy. Electron microscopy revealed that the structural transition correlated with an increase in the number of A beta 40 and A beta 42 aggregated that have a truncated fibrillar morphology. Finally, MAF increased A beta-induced toxicity of nerve growth factor (NGF)-differentiated PC-12 cells in the absence of Ca2+. The addition of Ca2+ to MAF-A beta incubations resulted in a moderate attenuation of toxicity possibly due to a reduction in A beta-cell interactions caused by extensive lateral aggregation of the MAF-A beta complexes. Our results indicate that A beta is generally susceptible to proteoglycan-mediated aggregation and fibril formation. We also propose that the MAF model system may be useful in delineating these interactions and represent a means to develop and examine potential inhibitors of the proteoglycan effects.
McLaurin
J
J
Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada. j.mclaurin@utoronto.ca
Franklin
T
T
Kuhns
W J
WJ
Fraser
P E
PE
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000302:isolation & purification / Q000494:pharmacology*; D002449:Cell Aggregation / Q000187:drug effects; D002942:Circular Dichroism; D005456:Fluorescent Dyes; D006025:Glycosaminoglycans; D006801:Humans; D008854:Microscopy, Electron; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000648:ultrastructure; D011161:Porifera; D017433:Protein Structure, Secondary; D011509:Proteoglycans / Q000494:pharmacology*; D051381:Rats; D012235:Rhodamines
D016229:Amyloid beta-Peptides; D015815:Cell Adhesion Molecules; D005456:Fluorescent Dyes; D006025:Glycosaminoglycans; D010446:Peptide Fragments; D011509:Proteoglycans; D012235:Rhodamines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C013065:cell aggregation factors; D020932:Nerve Growth Factor; D002118:Calcium