Attenuation of beta-amyloid-induced toxicity by sialic-acid-conjugated dendrimers: role of sialic acid attachment.

beta-Amyloid (Abeta) is the primary protein component of senile plaques in Alzheimer's disease and is believed to be associated with neurotoxicity in the disease. We and others have shown that Abeta binds with relatively high affinity to clustered sialic acid residues on cell surfaces and that removal of cell surface sialic acids attenuates Abeta toxicity. We have also shown that sialic acid functionalized dendrimeric polymers can act as mimics of cell surface sialic acid clusters and attenuate Abeta-induced neurotoxicity. In the current study, we prepared sialic-acid-conjugated dendrimers using a physiologically relevant attachment of the sialic acid to the dendrimeric termini, and evaluated the Abeta toxicity attenuation properties of the dendrimers. We compared performance of sialic-acid-conjugated dendrimeric polymers in which the sialic acid moieties were attached to dendrimeric termini via the anomeric hydroxyl group of the sialic acid, a physiological attachment, to polymers in which the attachment was made via the carboxylic acid group on the sialic acid, a non-physiological attachment. This work enhances our understanding of Abeta-cell surface binding and is a step towards the development of new classes of sequestering agents as therapeutics for the prevention of Abeta toxicity in AD.