(568x) Investigating the Interaction of A-Beta with Biologically Relevant Cyclic Sugars

A number of investigators, including ourselves, have suggested that A£] binds to cell membranes through interaction with cell surface gangliosides or glycoproteins containing sialic acid. Numerous studies have shown that the binding affinity of A£] to the membrane was higher when multiple sialic acids were present, either because of clustering of gangliosides or because of the degree of sialylation of the gangliosides. Based on this evidence, we synthesized a number of membrane mimetic multivalent sialic acid polymers, which, when added to cells in culture were found to attenuate toxicity. These materials also bound to A£] with high affinity (on the order of 107 to 108 M-1 association binding constants, compared to 106-107 M-1 for sialic acid containing membranes to A£]). These materials have been successful in attenuating A£] toxicity. However, the effectiveness of these materials displayed an unexpected dependence on the concentration of A£]. At high concentrations of A£], the sialic acid polymers were less effective at attenuating toxicity, regardless of polymer concentration, even when normalized. In addition, while valency of the sugar attached to the backbone polymer was highly correlated with ability of these materials to attenuate A?" toxicity, the energy of interaction between the A?" and the polymers could not simply be explained as an additive function of the number of sialic acids, suggesting that more complex intermolecular interactions between A?" and the sialic acid polymer were occurring that we could not explore in these earlier systems. We therefore have investigated multiple different cyclic biological sugars to determine their binding affinity to A£] for use in developing for effective membrane mimics.