Glycosaminoglycan and proteoglycan inhibit the depolymerization of β2-microglobulin amyloid fibrils in vitro

Background. Although several kinds of evidence suggest that glycosaminoglycans (GAGs) and proteoglycans (PGs) may contribute to the development of beta(2) -microglobulin-related (Abeta(2) m) amyloidosis, the precise roles of these molecules for the development of Abeta(2) m amyloidosis are poorly understood. Methods. We investigated the effects of GAGs and PGs on the depolymerization of Abeta(2) m amyloid fibrils at a neutral pH, as well as on the formation of the fibrils at an acidic pH in vitro, using fluorescence spectroscopy with thioflavin T and electron microscopy. Results. Depolymerization of Abeta(2) m amyloid fibrils at pH 7.5 at 37degreesC was inhibited dose-dependently by the presence of some GAGs (heparin, dermatan sulfate, or heparan sulfate) or PGs (biglycan, decorin, or keratan sulfate proteoglycan). Electron microscopy revealed that a significant amount of Abeta(2) m amyloid fibrils remained in the reaction mixture with some lateral aggregation. Second, when monomeric beta(2) m was incubated with aggrecan, biglycan, decorin, or heparin at pH 2.5 at 37degreesC for up to 21 days, the thioflavin T fluorescence increased depending on dose and time. Electron microscopy revealed the formation of rigid and straight fibrils similar to Abeta(2) m amyloid fibrils in beta(2) m incubated with biglycan for 21 days. Conclusion. These results suggest that some GAGs and PGs could enhance the deposition of Abeta(2) m amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of beta(2) m in the fibrils, as well as by acting as a scaffold for the polymerization of beta(2) m into the fibrils.