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

• Published in: Biochimica et biophysica acta 2012-10, Vol.1820 (10), p.1475-1480
• Main Authors: Dhavale, Dhruva, Henry, James E.
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Amyloid beta-Peptides - toxicity; Amyloid-beta toxicity; Antiparkinson Agents - isolation & purification; Antiparkinson Agents - pharmacology; Antiparkinson Agents - therapeutic use; blood-brain barrier; Carbohydrate Metabolism - physiology; Carbohydrates - chemistry; Carbohydrates - pharmacology; Carbohydrates - therapeutic use; cell membranes; Cell Survival - drug effects; Chitosan; Chitosan - chemistry; Chitosan - metabolism; Chitosan - pharmacology; Chitosan - therapeutic use; colorimetry; Cytoprotection - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fourier transform infrared spectroscopy; Ganglioside; Humans; Models, Biological; N-Acetylneuraminic Acid - analogs & derivatives; N-Acetylneuraminic Acid - isolation & purification; N-Acetylneuraminic Acid - pharmacology; N-Acetylneuraminic Acid - therapeutic use; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Osmolar Concentration; oxygen; pathogenesis; Sialic acid analog; sialic acids; Subgroups and substructure; Therapeutics for Alzheimer's disease; toxicity; Tumor Cells, Cultured
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.04.018

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. 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. 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. 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. Oxygen atom plays crucial role on therapeutic effectiveness. This work can help as a general guideline for further therapeutic development. ► Successful decoration of chitosan by different sialic acid analogs. ► Results show change in intrinsic toxicity before and after complexation of sugars. ► Demonstrated how unique structures effect Aβ toxicity attenuation. ► Results show importance of oxygen substitution and multi-OH tail of sialic acid. ► Results indicate oxygen containing structures will show therapeutic effectiveness.