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

BACKGROUND

Amyloid-beta peptide (Aβ) 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 Aβ or interfere with Aβ interaction/binding to cells have been investigated as a means to reduce the pathological effects of Aβ.

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 Aβ 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 Aβ binding.

CONCLUSIONS

Successfully produced compounds that showed varying degree of efficacy in attenuating Aβ toxicity to cells in culture. This work elucidates the impact that certain structures of sialic acid and its analogs can have on Aβ 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.