posted on 2021-05-24, 16:35authored byJay M. Pittman, Atul K. Srivastava, Christopher T. Boughter, Bharat Somireddy Venkata, Jonathan Zerweck, Patrick C. Moore, Izabela Smok, Marco Tonelli, Joseph R. Sachleben, Stephen C. Meredith
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.