title: Capping of aβ42 oligomers by small molecule inhibitors.
abstract: Aβ42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimer's 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 Aβ42 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 ~10-15 nm. The similar diameters suggest that the low MW species stack to form the high MW oligomers. The ability of Aβ42 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 Aβ42 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 Aβ42 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 Aβ oligomers provides insights into the mechanism of inhibition and the pathway of Aβ aggregation.
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University , Stony Brook, New York 11794-5215, United States.
authors.forename: Ziao
authors.initials: Z
authors.lastname: Fu
authors.forename: Darryl
authors.initials: D
authors.lastname: Aucoin
authors.forename: Mahiuddin
authors.initials: M
authors.lastname: Ahmed
authors.forename: Martine
authors.initials: M
authors.lastname: Ziliox
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry; D003474:Curcumin / Q000737:chemistry*; D006801:Humans; D007213:Indomethacin / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D066329:Protein Aggregates; D017434:Protein Structure, Tertiary; D013467:Sulindac / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D013467:Sulindac; C025462:sulindac sulfide; D003474:Curcumin; D007213:Indomethacin