(182e) Development of Novel Sialic Acid Containing Polymers for Use in Alzheimer's Disease

β-amyloid peptide (Aβ), the primary protein component of senile plaques in Alzheimer's disease (AD), plays an important role in neurotoxicity and is a marker for disease progression. Increasing evidence, both in our lab and others, indicates that Aβ binds with relatively high affinity to clustered sialic acid residues on cell surfaces. We hypothesize that multivalent sialic acid containing polymers can be designed with sufficiently high Aβ affinity that they will be useful in Aβ toxicity inhibition.

We have prepared two types of sialic acid containing polymers, one using generation 2, 3 and 4 polyamidoamine dendrimers conjugated with sialic acid, and the second using short oliogosaccharides terminated with sialic acid and crosslinked with glcidyl methacrylate. Synthesis and percent sialic acid labeling were characterized by FTIR, NMR, and a colorimetric assay. We have examined the Aβ binding affinity and toxicity attenuation properties of sialic acid modified dendrimers and cross linked oligosaccharides. For sialic acid conjugated dendrimers, Aβ toxicity attenuation was achieved at dendrimer concentrations of 10.5±0.2 nM dendrimer. Binding affinity was estimated at near 10^-8> M^-1. While we have not yet specifically measured the toxicity inhibition constant for the crosslinked multivalent sialic acid containing polymers, we have shown that the polymers significantly attenuated 20 μM Aβ toxicity at concentrations per mole of sialic acid of 250 and 500 μM.

This work could lead to the development of new therapeutics for the use in Alzheimer's disease and help elucidate the role of cell surface sialic acids in Aβ toxicity associated with the disease.