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 (A beta) fibrils that are associated with a variety of macromolecular species, including dermatan sulfate proteoglycan and heparan sulfate proteoglycan. The latter has been shown recently to bind tightly to both amyloid precursor protein and A beta, and this binding has been attributed largely to the interaction of the core protein of heparan sulfate proteoglycan with A beta and its precursor. Here we have examined the ability of synthetic A beta s to bind to and interact with the glycosaminoglycan moieties of proteoglycans. A beta(1-28) associates with heparin, heparan sulfate, 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 centrifugation. The ability of both A beta(1-28) and A beta(1-40) to bind glycosaminoglycans is pH-dependent, with increasing interaction as the pH values fall below neutrality and very little binding at pH 8.0. The pH profile of heparin-induced aggregation of A beta(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 A beta sequence reveals a consensus heparin-binding domain at residues 12-17, and this motif contains histidines at positions 13 and 14 that may be involved in the interaction with glycosaminoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)
Brunden
K R
KR
Discovery Research Group, Gliatech Inc., Cleveland, Ohio 44122.
Richter-Cook
N J
NJ
Chaturvedi
N
N
Frederickson
R C
RC
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002846:Chromatography, Affinity; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013552:Swine
D016229:Amyloid beta-Peptides; D006025:Glycosaminoglycans; D006493:Heparin; D006497:Heparan Sulfate; D009842:Oligopeptides; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C084359:amyloid beta-protein (13-17)