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 fi brils, accelerate formation and maintain their stability. To model their in teraction we investigated the binding of a sulfated proteoglycan derived fr om a natural source; marine sponge microciona prolifera aggregation factor (MAF). This species-specific re-aggregation of sponge cells has two-functio nal properties, a Ca2+ independent cell binding activity and a Ca2+ depende nt self-aggregation. It has been shown that a novel sulfated disaccharide a nd a pyruvylated trisaccharide are important in the Ca2+-dependent MAF aggr egation. Aggregation demonstrated by homophilic binding of MAF subunits may be chemically distinct from other heterotypic binding effects. We investig ated A beta-MAF interactions and show that MAF induces a structural transit ion in A beta 40 and A beta 42 om random to beta-structure as detected by c ircular dichroism spectroscopy. Electron microscopy revealed that the struc tural 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)-differen tiated PC-12 cells in the absence of Ca2+. The addition of Ca2+ to MAF-A be ta incubations resulted in a moderate attenuation of toxicity possibly due to a reduction in A beta-cell interactions caused by extensive lateral aggr egation of the MAF-A beta complexes. Our results indicate that AP is genera lly susceptible to proteoglycan-mediated aggregation and fibril formation. We also propose that the MAF model system may be useful in delineating thes e interactions and represent a means to develop and examine potential inhib itors of the proteoglycan effects.