Alzheimer's disease (AD) is associated with the accumulation of β-amyloid (Aβ) plaques in brain. The oligomeric aggregates of Aβ (AβOs) have emerged as important therapeutic targets due to their neurotoxicity to synaptic function. Very recently, we have developed a reverse micelle (RM) system to prepare AβOs with a monomorphic structure, where the RMs are exploited as nano-incubators to control the aggregation state of Aβ.1 We found that the advantages of using RMs to prepare AβOs are several folded. First, the 13C NMR line widths of the 13C enriched AβOs revealed that the structural order of the AβOs prepared in RMs are comparable to that of Aβ fibrils. Second, the fusion and fission of RMs allow the material transfer among RMs. Thus, RM is an ideal device for the study of the protein–protein interactions associated with amyloidogenic peptides. Third, by a judicious choice of the chemical compositions, one can actively control the size of the RMs. Experimentally, we were able to prepare AβOs of 10 nm in diameter. The solid-state NMR data indicated that the motional dynamics are different between the 10- and 23-nm AβOs, whereas the molecular structure of the b-sheet regions were largely the same. Finally, our RM systems allowed the preparation of the AβOs using brain tissue-derived Aβ aggregates as seeds. We successively amplified brain-derived AβOs through seven cycles, resulting in an increase of brain extract Aβ from picogram to microgram levels. Preliminary results showed that signal splitting in the cross peaks occurred for the AD patient brain-derived AβOs. With the aid of RM systems, we achieved a precise control of the aggregation state of Aβ, allowing for the structural characterization of brain-derived AβOs. The use of RMs provide a novel platform for characterizing AβOs and sheds light on the structural features associated with the pathogenic oligomeric aggregates of Aβ.
References:
(1) Chang, H.-W.; Ma, H.-I.; Wu, Y.-S.; Lee, M.-C.; Yuan, E. C.-Y.; Huang, S.-J.; Cheng, Y.-S.; Wu, M.-H.; Tu, L.-H.; Chan, J. C. C. Site Specific NMR Characterization of Abeta-40 Oligomers Cross Seeded by Abeta-42 Oligomers. Chem. Sci. 2022, 13 (29), 8526–8535. https://doi.org/10.1039/D2SC01555B.