{"doi":"10.1101/2023.10.05.561069","title":"Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy","abstract":"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 resolution, 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":397455,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8464,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":117572,"name":"Alexey G. Murzin","orcid":null,"position":1,"is_corresponding":false},{"id":331722,"name":"Sew‐Yeu Peak‐Chew","orcid":"0000-0002-7602-6384","position":2,"is_corresponding":false},{"id":818431,"name":"Catarina Franco","orcid":"0000-0003-2288-1518","position":3,"is_corresponding":false},{"id":268829,"name":"Kathy L. Newell","orcid":"0000-0002-1648-7357","position":4,"is_corresponding":false},{"id":268832,"name":"Bernardino Ghetti","orcid":"0000-0002-1842-8019","position":5,"is_corresponding":false},{"id":71017,"name":"Michel Goedert","orcid":"0000-0002-5214-7886","position":6,"is_corresponding":false},{"id":614851,"name":"Sjors H. W. Scheres","orcid":"0000-0002-0462-6540","position":7,"is_corresponding":false},{"id":818305,"name":"Yang Yang","orcid":"0000-0001-8912-7240","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T01:19:39.497368Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}