Interactions of Alzheimer amyloid‐β peptides with glycosaminoglycans: Effects on fibril nucleation and growth

Abstract

Proteoglycans and their constituent glycosaminoglycans are associated with all amyloid deposits and may be involved in the amyloidogenic pathway. In Alzheimer’s disease, plaques are composed of the amyloid‐β peptide and are associated with at least four different proteoglycans. Using CD spectroscopy, fluorescence spectroscopy and electron microscopy, we examined glycosaminoglycan interaction with the amyloid‐β peptides 1–40 (Aβ40) and 1–42 (Aβ42) to determine the effects on peptide conformation and fibril formation. Monomeric amyloid‐β peptides in trifluoroethanol, when diluted in aqueous buffer, undergo a slow random to amyloidogenic β sheet transition. In the presence of heparin, heparan sulfate, keratan sulfate or chondroitin sulfates, this transition was accelerated with Aβ42 rapidly adopting a β‐sheet conformation. This was accompanied by the appearance of well‐defined amyloid fibrils indicating an enhanced nucleation of Aβ42. Incubation of preformed Aβ42 fibrils with glycosaminoglycans resulted in extensive lateral aggregation and precipitation of the fibrils. The glycosaminoglycans differed in their relative activities with the chondroitin sulfates producing the most pronounced effects. The less amyloidogenic Aβ40 isoform did not show an immediate structural transition that was dependent upon the shielding effect by the phosphate counter ion. Removal or substitution of phosphate resulted in similar glycosaminoglycan‐induced conformational and aggregation changes. These findings clearly demonstrate that glycosaminoglycans act at the earliest stage of fibril formation, namely amyloid‐β nucleation, and are not simply involved in the lateral aggregation of preformed fibrils or nonspecific adhesion to plaques. The identification of a structure–activity relationship between amyloid‐β and the different glycosaminoglycans, as well as the condition dependence for glycosaminoglycan binding, are important for the successful development and evaluation of glycosaminoglycan‐specific therapeutic interventions.