Combining electron and nuclear magnetic resonance to track Alzheimer's amyloid-beta oligomer-to-fibril conversion

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Project Summary/Abstract Aggregation of Aβ protein plays a central role in the pathogenesis of Alzheimer's disease. Aβ aggregation leads to the formation of soluble oligomers and insoluble fibrils. While amyloid fibrils are the main component of parenchymal plaques in Alzheimer's disease brains, the Aβ oligomers have been widely regarded as more toxic and more pathologically relevant. There is strong evidence supporting that at least some types of Aβ oligomers can undergo a conformational conversion to form fibrils. It is yet poorly understood how the oligomers could re-arrange their structures to form fibrils. In this proposed project, we will use a combination of electron and nuclear magnetic resonance to monitor structural changes during Aβ42 oligomer-to-fibril conversion. The Aβ42 oligomers will be prepared in the presence of low concentrations of detergent. These Aβ42 oligomers represent a type of stable oligomers, which convert to fibrils only in the presence of lipid vesicles. The oligomer-to-fibril conversion will be followed by performing EPR and NMR experiments at different time points. This study will provide insights into whether oligomers dissociate to monomers, which then nucleate to form fibril nuclei, or oligomers transition to the structure of fibril nuclei without dissociation. We will not only delineate the mechanism of Aβ aggregation, but also shed light on how to modulate this process as a way of therapeutic intervention.