High-resolution atomic force microscopy of soluble Aβ42 oligomers

Soluble oligomers and protofibrils are widely thought to be the toxic forms of the A beta 42 peptide associated with Alzheimer's disease. We have investigated the structure and formation of these assemblies using a new approach in atomic force microscopy (AFM) that yields images of hydrated proteins and allows the structure of the smallest molecular weight (MW) oligomers to be observed and characterized. AFM images of monomers, dimers and other low MW oligomers at early incubation times ( < 1 h) are consistent with a hairpin structure for the monomeric A beta 42 peptide. The low MW oligomers are relatively compact and have significant order. The most constant dimension of these oligomers is their height (similar to 1-3 nm) above the mica surface; their lateral dimensions (width and length) vary between 5 nm and 10 nm. Flat nascent protofibrils with lengths of over 40 nm are observed at short incubation times (<= 3 h); their lateral dimensions of 6-8 nm are consistent with a mass-per-length of 9 kDa/nm previously predicted for the elementary fibril subunit. High MW oligomers with lateral dimensions of 15-25 nm and heights ranging from 2-8 nm are common at high concentrations of A beta. We show that an inhibitor designed to block the sheet-to-sheet packing in A beta fibrils is able to cap the heights of these oligomers at similar to 4 nm. The observation of fine structure in the high MW oligomers suggests that they are able to nucleate fibril formation. AFM images obtained as a function of incubation time reveal a sequence of assembly from monomers to soluble oligomers and protofibrils. (c) 2006 Elsevier Ltd. All rights reserved.