Evaluation of sialic acid-analogs for the attenuation of amyloid-beta toxicity

Background: Amyloid-beta peptide (A beta) is the main constituent of senile plaques and is implicated in the pathogenesis of Alzheimer's disease (AD). To that end, agents which either sequester A beta or interfere with A beta interaction/binding to cells have been investigated as a means to reduce the pathological effects of A beta. Methods: Different structural analogs of sialic acid (N-acetylneuramic acid) were used to decorate a chitosan backbone using EDC chemistry. FTIR and colorimetric assays were used to characterize the complexes. The ability of these complexes to attenuate A beta toxicity was investigated in vitro using a model neuroblastoma cell line SH-SY5Y. Results: Oxygen substitution in ring structure is responsible for the increase in toxicity and increase in protective properties of the complexes. Also, the multi -OH tail present in sialic acid is critical to attenuate toxicity. Analogs show no protective properties which reinforces the conclusion that clustering of sugars in cellular membranes play a significant role in A beta binding. Conclusions: Successfully produced compounds that showed varying degree of efficacy in attenuating A beta toxicity to cells in culture. This work elucidates the impact that certain structures of sialic acid and its analogs can have on A beta binding. It will allow for more specific and detailed improvements in the therapeutic polysaccharide structures that can be developed and modified to overcome other shortcomings of AD therapeutic development, particularly of penetrating the blood-brain barrier. General significance: Oxygen atom plays crucial role on therapeutic effectiveness. This work can help as a general guideline for further therapeutic development. (c) 2012 Elsevier B.V. All rights reserved.