Cryo-EM structures of amyloid-β 42 filaments from human brains

• Published in: Science (American Association for the Advancement of Science) Vol. 375; no. 6577; pp. 167 - 172
• Main Authors: Yang, Yang, Arseni, Diana, Zhang, Wenjuan, Huang, Melissa, Lövestam, Sofia, Schweighauser, Manuel, Kotecha, Abhay, Murzin, Alexey G., Peak-Chew, Sew Y., Macdonald, Jennifer, Lavenir, Isabelle, Garringer, Holly J., Gelpi, Ellen, Newell, Kathy L., Kovacs, Gabor G., Vidal, Ruben, Ghetti, Bernardino, Ryskeldi-Falcon, Benjamin, Scheres, Sjors H. W., Goedert, Michel
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 14.01.2022
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer's disease; Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - ultrastructure; Animal models; Animals; Assembly; Brain; Brain Chemistry; Cognitive ability; Cryoelectron Microscopy; Electron microscopy; Female; Filaments; Gene Knock-In Techniques; Humans; Inhibitors; Male; Medical imaging; Mice; Microscopy; Middle Aged; Models, Animal; Models, Molecular; Neurodegenerative diseases; Neuroimaging; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - ultrastructure; Peptides; Protein Conformation; Protein Conformation, beta-Strand; Protein Domains; Protein Folding; Residues; Tau protein; Transmission electron microscopy; β-Amyloid
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abm7285

Alzheimer’s disease is characterized by a loss of memory and other cognitive functions and the filamentous assembly of Aβ and tau in the brain. The assembly of Aβ peptides into filaments that end at residue 42 is a central event. Yang et al . used electron cryo–electron microscopy to determine the structures of Aβ42 filaments from human brain (see the Perspective by Willem and Fändrich). They identified two types of related S-shaped filaments, each consisting of two identical protofilaments. These structures will inform the development of better in vitro and animal models, inhibitors of Aβ42 assembly, and imaging agents with increased specificity and sensitivity. —SMH In Alzheimer’s disease and other conditions, two structurally related protofilaments form type I and type II Aβ42 filaments. Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in App NL-F knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.