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

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Alzheimer Disease* ; Cerebral Amyloid Angiopathy*; Humans ; Amyloid beta-Peptides/chemistry ; Cryoelectron Microscopy ; Peptide Fragments ; Amyloid ; Plaque, Amyloid

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.
(© 2023. The Author(s).)

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MC-UP-A025-1013 United Kingdom MRC_ Medical Research Council; MC_UP_A025_1013 United Kingdom MRC_ Medical Research Council; MC-U105184291 United Kingdom MRC_ Medical Research Council; RF1 NS110437 United States NS NINDS NIH HHS; MC_U105184291 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; P30 AG072976 United States AG NIA NIH HHS

Keywords: Aβ40 filaments; Cerebral amyloid angiopathy; Electron cryo-microscopy; Leptomeninges

0 (Amyloid beta-Peptides)
0 (Peptide Fragments)
0 (Amyloid)

Date Created: 20231204 Date Completed: 20231206 Latest Revision: 20250530

20250530

PMC10694933

10.1186/s40478-023-01694-8

38049918