Aβ42 fibril formation from predominantly oligomeric samples suggests a link between oligomer heterogeneity and fibril polymorphism.

Amyloid-beta (A beta) oligomers play a central role in the pathogenesis of Alzheimer's disease. Oligomers of different sizes, morphology and structures have been reported in both in vivo and in vitro studies, but there is a general lack of understanding about where to place these oligomers in the overall process of A beta aggregation and fibrillization. Here, we show that A beta 42 spontaneously forms oligomers with a wide range of sizes in the same sample. These A beta 42 samples contain predominantly oligomers, and they quickly form fibrils upon incubation at 37 degrees C. When fractionated using ultrafiltration filters, the samples enriched with smaller oligomers form fibrils at a faster rate than the samples enriched with larger oligomers, with both a shorter lag time and faster fibril growth rate. This observation is independent of A beta 42 batches and hexafluoroisopropanol treatment. Furthermore, the fibrils formed by the samples enriched with larger oligomers are more readily solubilized by epigallocatechin gallate, a main catechin component of green tea. These results suggest that the fibrils formed by larger oligomers may adopt a different structure from fibrils formed by smaller oligomers, pointing to a link between oligomer heterogeneity and fibril polymorphism.