Amyloid-β Forms Fibrils by Nucleated Conformational Conversion of Oligomers

Aβ amyloidogenesis is reported to occur via a nucleated polymerization mechanism, if so the energetically unfavorable oligomeric nucleus should be very hard to detect. However, many laboratories have detected early non-fibrillar Aβ oligomers without observing amyloid fibrils, suggesting a mechanistic revision may be needed. Herein, we introduce Cys-Cys-Aβ(1-40) that cannot bind to the latent fluorophore FlAsH as a monomer, but is capable of binding FlAsH as an non-fibrillar oligomer or as a fibril, rendering the conjugates fluorescent. FlAsH monitoring of Cys-Cys-Aβ(1-40) aggregation provides compelling evidence that Aβ(1-40) very rapidly and efficiently forms spherical oligomers in vitro (85% yield) that are kinetically competent to slowly convert to amyloid fibrils by a nucleated conformational conversion mechanism (seedable). Moreover, this methodology demonstrated that plasmalogen ethanolamine vesicles eliminate the proteotoxicity-associated oligomerization phase of Aβ amyloidogenesis, while allowing fibril formation, rationalizing how low plasmalogen ethanolamine levels in the brain are epidemiologically linked to Alzheimer’s disease.