Nanodroplet Oligomers (NanDOs) of Aβ40

Using atomic force microscopy (AFM) and nuclear magnetic resonance (NMR), we describe small Aβ40 oligomers, termed nanodroplet oligomers (NanDOs), which form rapidly and at Aβ40 concentrations too low for fibril formation. NanDOs were observed in putatively monomeric solutions of Aβ40 (e.g., by size exclusion chromatography). Video-rate scanning AFM shows rapid fusion and dissolution of small oligomer-sized particles, of which the median size increases with peptide concentration. In NMR (¹³C HSQC), a small number of chemical shifts changed with a change in peptide concentration. Paramagnetic relaxation enhancement NMR experiments also support the formation of NanDOs and suggest prominent interactions in hydrophobic domains of Aβ40. Addition of Zn²⁺ to Aβ40 solutions caused flocculation of NanDO-containing solutions, and selective loss of signal intensity in NMR spectra from residues in the N-terminal domain of Aβ40. NanDOs may represent the earliest aggregated form of Aβ40 in the aggregation pathway and are akin to premicelles in solutions of amphiphilies.