Abstract
Amyloid-β (Aβ) 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 Aβ aggregation and fibrillization. Here, we show that Aβ42 spontaneously forms oligomers with a wide range of sizes in the same sample. These Aβ42 samples contain predominantly oligomers, and they quickly form fibrils upon incubation at 37°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 Aβ42 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.
Highlights
Protein aggregation is involved in a wide range of human diseases [1]
Some studies suggest that oligomers eventually are converted to amyloid fibrils [9,10] or form the building blocks of amyloid fibrils [11 –15], and other studies show that the amyloid fibrils can promote the formation of oligomers [16]
We checked the morphology of the Ab sample after buffer exchange using transmission electron microscopy (TEM), which shows that the Ab42 sample contains abundant oligomers
Summary
Protein aggregation is involved in a wide range of human diseases [1]. The end aggregation product is often the pathological. It has been well established that protein aggregation leads to the formation of soluble intermediates, which are often called oligomers These oligomers are shown to be more toxic than the amyloid fibrils in a variety of activity assays using cultured cells and transgenic animals (reviewed in [8]). Some studies suggest a fibrillization model of nucleated conformational conversion [9,10,30] This model starts with the formation of Ab oligomers, which convert to fibril nuclei. There are studies suggesting that Ab forms ringlike oligomers, which form the building blocks of amyloid fibrils [15,32,33] It is unclear how Ab aggregation proceeds in the brain. Ab42 fibrils formed by small and large oligomers appear to have different structural characteristics, suggesting a link between oligomer heterogeneity and fibril polymorphism
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