Site specific NMR characterization of abeta-40 oligomers cross seeded by abeta-42 oligomers

Abstract

Extracellular accumulation of β amyloid peptides of 40 (Aβ40) and 42 residues (Aβ42) has been considered as one of the hallmarks in the pathology of Alzheimer's disease. In this work, we are able to prepare oligomeric aggregates of Aβ with uniform size and monomorphic structure. Our experimental design is to incubate Aβ peptides in reverse micelles (RMs) so that the peptides could aggregate only through a single nucleation process and the size of the oligomers is confined by the physical dimension of the reverse micelles. The hence obtained Aβ oligomers (AβOs) are 23 nm in diameter and they belong to the category of high molecular-weight (MW) oligomers. The solid-state NMR data revealed that Aβ40Os adopt the structural motif of β-loop-β but the chemical shifts manifested that they may be structurally different from low-MW AβOs and mature fibrils. From the thioflavin-T results, we found that high-MW Aβ42Os can accelerate the fibrillization of Aβ40 monomers. Our protocol allows performing cross-seeding experiments among oligomeric species. By comparing the chemical shifts of Aβ40Os cross seeded by Aβ42Os and those of Aβ40Os prepared in the absence of Aβ42Os, we observed that the chemical states of E11, K16, and E22 were altered, whereas the backbone conformation of the β-sheet region near the C-terminus was structurally invariant. The use of reverse micelles allows hitherto the most detailed characterization of the structural variability of Aβ40Os.

Graphical abstract: Site specific NMR characterization of abeta-40 oligomers cross seeded by abeta-42 oligomers

Supplementary files

Article information

Article type
Edge Article
Submitted
17 Mar 2022
Accepted
12 Jun 2022
First published
22 Jun 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022, Advance Article

Site specific NMR characterization of abeta-40 oligomers cross seeded by abeta-42 oligomers

H. Chang, Ho-I. Ma, Y. Wu, M. Lee, E. Chung-Yueh Yuan, S. Huang, Y. Cheng, M. Wu, L. Tu and J. C. C. Chan, Chem. Sci., 2022, Advance Article , DOI: 10.1039/D2SC01555B

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