Poster Presentation 23rd International Society of Magnetic Resonance Conference 2023

Active size control of oligomeric aggregates of Aβ peptide (#218)

Chen-Tsen Yeh 1 , Han-Wen Chang 1 , Shing-Jong Huang 2 , Chun Chung Chan 1
  1. Department of Chemistry, National Taiwan University, Taipei, Taiwan
  2. Instrumentation Center, National Taiwan University, Taipei, Taiwan

The accumulation of β-amyloid (Aβ) in the brain is a defining characteristic of Alzheimer’s disease (AD). Oligomeric aggregates of Aβ in particular are of interest due to their neurotoxicity and ability to impair synaptic function. Recent advances in AD treatment include Lecanamab, a monoclonal antibody that selectively binds to soluble Aβ aggregates over monomers and insoluble fibrils, which has been approved by the FDA for its ability to target brain Aβ plaques and slow cognitive decline.[1] However, the size-structure-toxicity relationship of oligomeric Aβ aggregates remains unclear. We previously utilized a reverse micelle (RM) system to prepare oligomeric aggregates of Aβ40 with a uniform size of 23 nm in diameter, called RM23-Aβ40, which are structurally monomorphic.[2] In this study, we varied the ratio of organic phase and surfactant in the reverse micelle system and incubated Aβ40 monomer in RM for 7 days to prepare oligomeric aggregates of Aβ with a diameter of 10 nm, which we call RM10-Aβ40. Our results show that RM10-Aβ40 exhibits higher cell toxicity than RM23-Aβ40, and Thioflavin T (ThT) assay reveals a distinct lag phase compared to RM23-Aβ40, indicating differences in beta-sheet formation. To further investigate the structural information among these Aβ oligomers, we conducted solid-state NMR analysis on four 13C-enriched samples spanning residues E11 to V40. Although the overall full width at half maximum (FWHM) is comparable between RM23-Aβ40 and RM10-Aβ40, there is strong evidence that the chemical shift is altered in the β1 and turn regions, and the intensity analysis shows that the motional dynamics of RM10-Aβ40 in certain regions, mostly charged residues, were higher than in RM23-Aβ40. Our findings suggest that the motional dynamics of oligomeric Aβ aggregates may play a critical role in aggregation kinetics and cell toxicity. This study provides experimental evidence comparing Aβ oligomers with active size control, emphasizing the importance of the size-structure-toxicity relationship in Aβ aggregates.

  1. van Dyck, C. H.; Swanson, C. J.; Aisen, P.; Bateman, R. J.; Chen, C.; Gee, M.; Kanekiyo, M.; Li, D.; Reyderman, L.; Cohen, S.; Froelich, L.; Katayama, S.; Sabbagh, M.; Vellas, B.; Watson, D.; Dhadda, S.; Irizarry, M.; Kramer, L. D.; Iwatsubo, T. Lecanemab in Early Alzheimer’s Disease. N. Engl. J. Med. 2023, 388 (1), 9–21.
  2. 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.