Structural Dynamics of Amyloid-ß Protofibrils and Actions of Anti-Amyloid-ß Antibodies as Observed by High-Speed Atomic Force Microscopy.
Nano Lett
; 23(13): 6259-6268, 2023 07 12.
Article
em En
| MEDLINE
| ID: mdl-37141711
ABSTRACT
Amyloid-ß (Aß) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used high-speed atomic force microscopy to observe the structural dynamics of Aß42 PF at the single-molecule level and the effect of lecanemab, an anti-Aß PF antibody with the positive results from Phase 3 Clarity AD. PF was found to be a curved nodal structure with stable binding angle between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PFs and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Aß aggregation process.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Revista:
Nano Lett
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Japão