Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy

If you need an accessible version of this item, please submit a remediation request.
Date
2023-12-04
Language
American English
Embargo Lift Date
Committee Members
Degree
Degree Year
Department
Grantor
Journal Title
Journal ISSN
Volume Title
Found At
Springer Nature
Abstract

We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 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 Aβ40 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 Aβ42 and blood vessel deposits of Aβ40 have distinct structures, supporting the view that Alzheimer's disease and cerebral amyloid angiopathy are different Aβ proteinopathies.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Yang Y, Murzin AG, Peak-Chew S, et al. Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. Acta Neuropathol Commun. 2023;11(1):191. Published 2023 Dec 4. doi:10.1186/s40478-023-01694-8
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Acta Neuropathologica Communications
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Final published version
Full Text Available at
This item is under embargo {{howLong}}