Alzheimer's disease (AD) is characterized by Heparin the presence of amyloid plaques in the AD brain. Comprised primarily of the 40- and 42-residue beta-amyloid (A beta) peptides, there is evidence that the heparan sulfate (HS) of heparan sulfate proteoglycans (HSPGs) plays a role in amyloid plaque formation and stability; however, details of the interaction of A beta peptides with HS are not known. We have characterized the interaction of heparin and heparin-derived oligosaccharides with a model peptide for the heparin- and HS-binding domain of A beta peptides (Ac-VHHQKLV-NH2; A beta(12-18)), with mutants of A beta(12-18), and with additional histidine-containing peptides. The nature of the binding interaction was characterized by NMR, binding constants and other thermodynamic parameters were determined by isothermal titration calorimetry (ITC), and relative binding affinities were determined by heparin affinity chromatography. The binding of A beta(12-18) by heparin and heparin-derived oligosaccharides is pH-dependent, with the imidazolium groups of the histidine side chains interacting site-specifically within a cleft created by a trisaccharide sequence of heparin, the binding is mediated by electrostatic interactions, and there is a significant entropic contribution to the binding free energy as a result of displacement of Na+ ions from heparin upon binding of cationic A beta(12-18). The binding constant decreases as the size of the heparin-derived oligosaccharide decreases and as the concentration of Na+ ion in the bulk solution increases. Structure-binding relationships characterized in this study are analyzed and discussed in terms of the counterion condensation theory of the binding of cationic peptides by anionic polyelectrolytes.