Small Amphipathic Molecules Modulate the Secondary Structure and Amyloid Fibril Forming Kinetics of the Alzheimer’s Disease Peptide Aß1-42

Amyloid fibril formation is associated with a number of debilitating systemic and neurodegenerative diseases. One of the most prominent is Alzheimer’s disease in which aggregation and deposition of the Aß peptide occurs. Aß is widely considered to mediate the extensive neuronal loss observed in this disease through the formation of soluble oligomeric species, with the final fibrillar end-product of the aggregation process being relatively inert. Factors that influence the aggregation of these amyloid-forming proteins are therefore very important. We have screened a library of 96 amphipathic molecules for effects on Aß1-42 aggregation and self-association. We find, using Thioflavin T fluorescence and electron microscopy assays, that 30 of the molecules inhibit the aggregation process, while 36 activate fibril formation. Several activators and inhibitors were subjected to further analysis using analytical ultracentrifugation and circular dichroism. Activators typically display a 1:10 peptide : detergent stoichiometry for maximal activation, while the inhibitors are effective at a 1:1 stoichiometry. Analytical ultracentrifugation and circular dichroism experiments show that activators promote a mixture of unfolded and "-sheet structures and rapidly form large aggregates, while inhibitors induce !-helical structures that form stable dimeric/trimeric oligomers. The results suggest that Aß1-42 contains at least one small molecule bindingsites, which modulates the secondary structure and aggregation processes. Further studies of the binding of these compounds to Aß may provide insight for developing therapeutic strategies aimed at stabilizing Aß in a favourable conformation. ______________________________________