Site specific NMR characterization of abeta-40 oligomers cross seeded by abeta-42 oligomers
Journal
Chemical science
Journal Volume
13
Journal Issue
29
Pages
8526
Date Issued
2022-07-29
Author(s)
Chang, Han-Wen
Ma, Ho-I
Wu, Yi-Shan
Lee, Ming-Che
Chung-Yueh Yuan, Eric
Huang, Shing-Jong
Cheng, Yu-Sheng
Wu, Meng-Hsin
Tu, Ling-Hsien
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.
Subjects
AMYLOID-BETA-PROTEIN; ATOMIC-RESOLUTION STRUCTURE; ALZHEIMERS-DISEASE; REVERSE MICELLES; FIBRIL FORMATION; STRUCTURAL BASIS; A-BETA-42; AGGREGATION; PEPTIDE; STATE
SDGs
Publisher
ROYAL SOC CHEMISTRY
Type
journal article