PH-DEPENDENT BINDING OF SYNTHETIC BETA-AMYLOID PEPTIDES TO GLYCOSAMINOGLYCANS

The senile plaques found within the cerebral cortex and hippocampus of the Alzheimer disease brain contain beta-amyloid peptide (Abeta) fibr ils that are associated with a variety of macromolecular species, incl uding dermatan sulfate proteoglycan and heparan sulfate proteoglycan. The latter has been shown recently to bind tightly to both amyloid pre cursor protein and Abeta, and this binding has been attributed largely to the interaction of the core protein of heparan sulfate proteoglyca n with Abeta and its precursor. Here we have examined the ability of s ynthetic Abetas to bind to and interact with the glycosaminoglycan moi eties of proteoglycans. Abeta(1-28) associates with heparin, heparan s ulfate, dermatan sulfate, and chondroitin sulfate. The interaction of these sulfated polysaccharides with the amyloid peptide results in the formation of large aggregates that are readily sedimented by centrifu gation. The ability of both Abeta(1-28) and Abeta(1-40) to bind glycos aminoglycans is pH-dependent, with increasing interaction as the pH va lues fall below neutrality and very little binding at pH 8.0. The pH p rofile of heparin-induced aggregation of Abeta(1-28) has a midpoint pH of approximately 6.5, suggesting that one or more histidine residues must be protonated for binding to occur. Analysis of the Abeta sequenc e reveals a consensus heparin-binding domain at residues 12-17, and th is motif contains histidines at positions 13 and 14 that may be involv ed in the interaction with glycosaminoglycans. This hypothesis is supp orted by the following observations: (a) Abeta(13-17) binds tightly to a heparin affinity column at pH 4.0, but not at pH 8.0; and (b) an Ab eta(13-17) in which histidine residues 13 and 14 have been replaced wi th serines does not bind to a heparin column at either pH 8.0 or 4.0. Together, the data indicate that Abeta is capable of binding to the gl ycosaminoglycan chains of proteoglycans, and such an interaction may b e relevant to the etiology and pathology of Alzheimer's disease.