Nucleation dynamics in amyloid-beta dimerization revealed by single-molecule fingerprinting.

Abstract

The aggregation of amyloid-beta (Aβ) peptides ( Aβ1-40 or Aβ1-42 ) is closely related to the pathology of Alzheimer's disease (AD). Soluble oligomers that appear during Aβ aggregation are primary neurotoxic species; however, their misfolding kinetics have yet to be determined. Here, we report a bottom-up construction of parallel and antiparallel Aβ1-40 dimers, the first oligomers formed during Aβ aggregation. We apply single-molecule mechanical unfolding in optical tweezers to investigate the dynamic structural evolution of these dimers at the single-amino-acid resolution. We observe three intermediates during the association and dissociation of individual Aβ1-40 dimers, with the diphenylalanine Aβ19-20 dimer having the highest formation probability. Our single-molecule fingerprinting method reveals that a known Aβ aggregation inhibitor, rosmarinic acid, can reduce Aβ1-40 dimerization by binding to the Aβ19-20 site. We anticipate that the molecular tool innovated in our study is extensible to investigating other amyloid aggregations responsible for a myriad of neurodegenerative diseases.