Doctor of Philosophy (PhD)
There is evidence that amyloid-beta (Aβ) toxicity is mediated through interactions and binding with neuronal surface sialic acids in Alzheimer’s disease (AD). The binding affinity is higher if the sialic acids are clustered and toxicity of Aβ was attenuated by removal of neuronal sialic acids. Thus, interfering with cell membrane-Aβ binding using biomimetics that could reproduce the clustered sialic acid structure could present us with a potential target for therapeutic intervention in AD. Based on this hypothesis, we developed several multifunctionalized sialic acid labeled chitosan compounds of different valency, or number of sialic acid per chitosan molecule, to attenuate Aβ toxicity. A cross-linker, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) was used, which provided control over the degree of labeling of chitosan. After characterization, the ability of the complexes to attenuate toxicity of Aβ(1-40) was investigated in vitro. We found that all linear polysialylated complexes showed significant ability to attenuate Aβ toxicity, with optimum balance between intrinsic toxicity and protection around 37% labeling of chitosan. Moreover, unlabeled chitosan also showed some level of protective properties to the labeled compounds. Then, four biological sugars that are structural analogs of sialic acid (N-Acetylneuraminic acid) were used to decorate approximately 35% of the chitosan backbone using EDC chemistry. After characterization, the ability of these sugar complexes to attenuate toxicity of Aβ was investigated in vitro. We investigated whether sugars other than sialic acid provided better toxicity attenuation and attempted to understand the impact of sub-structures or unique –R groups of sialic acid and its analogs in Aβ toxicity attenuation. Our results show that oxygen substitution in the ring structure contributes to the intrinsic toxicity but also plays a role in Aβ toxicity attenuation. Similarly, the multi –OH tail present in sialic acid plays an important role in Aβ toxicity attenuation. This approach of designing effective biomimetics and of determining the structure-activity relationship has relevance with respect to the development of new intelligent class of therapeutic agents for AD. Although this work focuses on AD, this approach can be extended to other diseases involving misfolded proteins.
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Dhavale, Dhruva Dilip, "Efficacy of Multifunctionalized Saccharide Constructs for the Attenuation of Amyloid-beta Toxicity" (2012). LSU Doctoral Dissertations. 2446.
Benton, Michael G.