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SINGLE-MOLECULE ANALYSIS OF ALZHEIMER'S β-PEPTIDE OLIGOMER DISASSEMBLY AT PHYSIOLOGICAL CONCENTRATION

The diffusible soluble oligomeric amyloid β-peptide (Aβ) has been identified as a toxic agent in Alzheimer’s disease that can cause synaptic dysfunction and memory loss, indicating its role as potential therapeutic targets for AD treatment. Recently an oligomer-specific sandwich biotin-avidin interaction based assay identified the Aβ oligomer dissociation potency of a series of dihydroxybenzoic acid (DHBA) isomers. Because the sandwich assay is an ensemble method providing limited size information, fluorescence correlation spectroscopy (FCS) was employed to provide single molecule resolution of the disassembly mechanism.
Using FCS coupled with atomic force microscopy, we investigated the size distribution of fluorescein labeled synthetic Aβ oligomers at physiological concentrations, and monitored in real time the change of size and mole fraction of oligomers in the presence of dissociating agents or conditions. The higher-order dissociation process caused by DHBA isomers produced no transient oligomeric intermediates, a desirable feature for an anti-oligomer therapeutic. Urea and guanidine hydrochloride, in contrast, produced a linear dissociation with a progressive decrease of size and mole fraction of oligomers. FCS allows the facile distinction of small molecule Aβ oligomer dissociators that do not produce stable potentially toxic oligomeric Aβ intermediates.

Identiferoai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:chemistry_etds-1033
Date01 January 2014
CreatorsChen, Chen
PublisherUKnowledge
Source SetsUniversity of Kentucky
Detected LanguageEnglish
Typetext
Formatapplication/pdf
SourceTheses and Dissertations--Chemistry

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