Soluble oligomers
of amyloid-forming proteins are implicated as
toxic species in the context of several neurodegenerative diseases.
Since the size and shape of these oligomers influence their toxicity,
their biophysical characterization is essential for a better understanding
of the structure–toxicity relationship. Amyloid oligomers are
difficult to characterize by conventional approaches due to their
heterogeneity in size and shape, their dynamic aggregation process,
and their low abundance. This work demonstrates that resistive pulse
measurements using polymer-coated solid-state nanopores enable single-particle-level
characterization of the size and shape of individual αSyn oligomers
in solution within minutes. A comparison of the resulting size distribution
with single-particle analysis by transmission electron microscopy
and mass photometry reveals good agreement with superior resolution
by nanopore-based characterization. Moreover, nanopore-based analysis
has the capability to combine rapid size analysis with an approximation
of the oligomer shape. Applying this shape approximation to putatively
toxic oligomeric species that range in size from 18 ± 7 aggregated
monomers (10S) to 29 ± 10 aggregated monomers (15S) and in concentration
from picomolar to nanomolar revealed oligomer shapes that agree well
with previous estimates by cryo-EM with the added advantage that nanopore-based
analysis occurs rapidly, in solution, and has the potential to become
a widely accessible technique.