A sulfated proteoglycan aggregation factor mediates amyloid-β peptide fibril formation and neurotoxicity

Abstract

Proteoglycans are associated with senile plaques in Alzheimer's disease and may be involved in Aβ fibril formation and plaque formation. In vitro, glycosaminoglycans have been shown to inhibit the proteolysis of Aβ 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 Cd2+independent cell binding activity and a Ca2+ dependent self-aggregation. It has been shown that a novel sulfated disaccharide andapyruvylatedtrisac-charide are important in the Ca2+-dependent MF aggregation. Aggregation demonstrated by homophilic binding of U4F subunits may be chemically distinct from other heterotypic binding effects. We investigated Aβ-MAF interactions and show that MAF induces a structural transition in Aβ40 and Aβ42 from random to β-structure as detected by circular dichroism spectroscopy. Electron microscopy revealed that the structural transition correlated with an increase in the number of Aβ40 and Aβ42 aggregated that have a truncated Jibrillar morphology. Finally, MAF increased Aβ-induced toxicity of nerve growth factor (NGF)-differentiared PC-12 cells in the absence of Ca2+. The addition of Ca2+ to MAF-Aβ incubations resulted in a moderate attenuation of toxicity possibly due to a reduction in Aβ-cell interactions caused by extensive lateral aggregation of the MAF-Aβ complexes. Our results indicate that Aβ is generaliy 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.