We describe here an assessment of the hydrophobicity and solvent accessibility of Aβ species upon aggregation and use those experiments to guide development of a model that examines Aβ toxicity. Hydrophobicity specific fluorescence probes were used to detect the exposure of hydrophobic residues of the different Aβ aggregation species. Hydrogen exchange mass spectrometry was used to examine the solvent accessibility of the backbone of different Aβ aggregation species. The results reveal that the transition between the monomer to the mature fibril is smooth, and that the intermediate aggregate does not seem to have unique structural features. Moreover, it seems that the intermediate has lower level characteristics of the mature fibril, implying that the intermediate is a smaller fibril and is not structurally different. This result may imply that the intermediate appears more toxic than the fibril due to its higher mobility and higher concentration, and not due to differences in structure specific interactions of the different aggregated species. We estimated the rate of reaction between Aβ aggregates and neurons, assuming that the reaction was diffusion-limited reaction. Using this simple model and information about the geometry of the fibrils and oligomers, we can explain the difference in biological activity of these different Aβ aggregates.
In the light of our hypothesis that the toxic intermediate and fibril share the same molecular level structure, we are currently using atomic-level docking to predict the interaction of Aβ fibril and aggregate species with other small molecules and proteins. With these results, we hope to be able to infer differences in interaction associated with self assembly and those associated with toxicity.