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

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.

Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

“…These observations reproduce our previous findings using HS-AFM [5] (with all dimension values to within 5-10 %) and indicate the existence of oligomers in samples prepared from Aβ42 peptide solutions. The latter is not uncommon and likely due to either their rapid formation in solution [6], or incomplete disaggregation of the lypholized peptide [7]. Similarly to our previous study [6], a few smaller species appear transiently, i.e.…”

“…The latter is not uncommon and likely due to either their rapid formation in solution [6], or incomplete disaggregation of the lypholized peptide [7]. Similarly to our previous study [6], a few smaller species appear transiently, i.e. only observed in ~ 2 consecutive frames before leaving the scan area, and show an indistinct morphology likely owing to artefact when tracking fast moving objects [8].…”

“…Supplementary Figure 5. Movie sequence shown in Figure 3 with labelling of (A) individual existing oligomers (1,2,3) before injection and (B) new nuclei (4,5,6)…”

Capturing Amyloid-β Oligomers by Stirring with Microscaled Iron Oxide Stir Bars into Magnetic Plaques to Reduce Cytotoxicity toward Neuronal Cells

“…The total and mean areas of the stained mpAβ 42 were quantified with the functions of Image-Pro Plus 6.0 ( n = 10). The morphology of mpAβ 42 was examined by TEM, scanning probe microscopy (SPM, tapping mode, Bruker, Model-Dimension Icon, Camarillo, CA, USA) and atomic force microscope (AFM, Bruker, Santa Barbara, CA, USA) [ 29 , 30 , 31 , 32 ].…”

Glycodendrimers as Potential Multitalented Therapeutics in Alzheimer’s Disease

“…Non-amyloidogenic pathway, where APP is subjected to consecutive cleavage by α-and γ-secretases that cut APP within the Aβ fragment 2. Amyloidogenic APP pathway, where APP is subjected to cleavage by β-and γ-secretases generating Aβ, a mix of short peptides ranging from 38 to 43 amino acids in length able to form polymorphous aggregates, so-called oligomers, and fibrils [6] APP processing is regulated by neuronal activity, and neuronal activity may favor β-secretase-mediated amyloidogenic cleavage of APP during which Aβ proteins are generated [7]. It was accepted that after APP cleavage, Aβ peptides are first secreted, and then, extracellularly, soluble Aβ peptides aggregate into amyloid plaques.…”