Cryo-EM structures of Aß40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy.
Acta Neuropathol Commun
; 11(1): 191, 2023 12 04.
Article
en En
| MEDLINE
| ID: mdl-38049918
ABSTRACT
We used electron cryo-microscopy (cryo-EM) to determine the structures of Aß40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments. However, our new structures, solved to a resolution of 2.4 Å, revealed differences in the sequence assignment that redefine the fold of Aß40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of Aß42 and blood vessel deposits of Aß40 have distinct structures, supporting the view that Alzheimer's disease and cerebral amyloid angiopathy are different Aß proteinopathies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Angiopatía Amiloide Cerebral
/
Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Revista:
Acta Neuropathol Commun
Año:
2023
Tipo del documento:
Article
País de afiliación:
Reino Unido