Identifier

etd-09152009-013617

Degree

Master of Science in Chemical Engineering (MSChE)

Department

Chemical Engineering

Document Type

Thesis

Abstract

Amyloid-beta (Aβ), a 39 to 43 amino acid long peptide, is the primary species identified in senile plaques associated with Alzheimer’s disease (AD) and has been implicated in the neurotoxicity associated with AD. It is believed that Aβ toxicity is mediated through the interaction with neuronal membranes. A variety of evidence indicates that 1) Aβ may bind to the cell surface sialic acids, 2) the affinity of this interaction is higher if the gangliosides or sialic acids on the cell surface are clustered, 3) the removal of the surface sialic acids attenuate Aβ toxicity. Based on this data, we hypothesized that a biomimetic compound could be synthesized which would reproduce the clustered sialic acid structure of the cell surface, having antibody-like affinity towards Aβ, thus competing with the cell surface for Aβ binding. Our technique relies on attacking the theoretical “bottleneck” region in the Alzheimer’s process, i.e. the interaction of Aβ with neurons. This area can be considered as a bottleneck as there are several mechanisms that can transform the Aβ peptide into its toxic form. Also, the exact toxic form of Aβ peptide that attacks neurons is not agreed upon. However, it is agreed that preventing neuronal interaction prevents toxicity making the Aβ-cell interaction the “bottleneck” region. To explore this hypothesis further, we developed different sialic acid labeled compounds of different valency or number of sialic acids per molecule to attenuate Aβ toxicity. For this purpose, chitosan was used as a carrier molecule for sialic acids. EDC along with Sulfo-NHS was used as a cross-linker to couple the sialic acids with chitosan, with control over the degree of labeling. After verifying the presence of sialic acids on chitosan, the ability of this sialic acid-chitosan complex to attenuate the toxicity of aggregated Aβ was investigated in-vitro. Preliminary results indicate that the complex synthesized is biocompatible. Also, the results suggested that the compound has Aβ toxicity attenuating properties. Further studies will help elucidate the role of cell-surface sialic acids in Aβ toxicity. Drugs available today are merely symptoms alleviating and thus, these results can have implications in the design of intelligent compounds that can bind pathogenic Aβ for the treatment of Alzheimer’s disease.

Date

2009

Document Availability at the Time of Submission

Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide.

Committee Chair

Henry, James E.

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