Capping of Aβ42 Oligomers by Small Molecule Inhibitors

A beta 42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimers disease. The oligomers have been reported to be more toxic to neurons than fibrils, and have been targeted by a wide range of small molecule and peptide inhibitors. With single touch atomic force microscopy (AFM), we show that monomeric A beta 42 forms two distinct types of oligomers, low molecular weight (MW) oligomers with heights of 1-2 nm and high MW oligomers with heights of 3-5 nm. In both cases, the oligomers are disc-shaped with diameters of similar to 10-15 nm. The similar diameters suggest that the low MW species stack to form the high MW oligomers. The ability of A beta 42 inhibitors to interact with these oligomers is probed using atomic force microscopy and NMR spectroscopy. We show that curcumin and resveratrol bind to the N-terminus (residues 5-20) of A beta 42 monomers and cap the height of the oligomers that are formed at 1-2 nm. A second class of inhibitors, which includes sulindac sulfide and indomethacin, exhibit very weak interactions across the A beta 42 sequence and do not block the formation of the high MW oligomers. The correlation between N-terminal interactions and capping of the height of the A beta oligomers provides insights into the mechanism of inhibition and the pathway of A beta aggregation.