Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain

Yang, Y. `; Arseni, D.; Zhang, W.; Huang, M.; Lövestam, S.; Schweighauser, M.; Kotecha, A.; Murzin, A. G.; Peak-Chew, S. Y.; Macdonald, J.; Lavenir, I.; Garringer, H. J.; Gelpi, E.; Newell, K. L.; Kovacs, G. G.; Vidal, R.; Ghetti, B.; Falcon, B.; Scheres, S.; Goedert, M.

doi:10.1101/2021.10.19.464936

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bioRxiv · 10.1101/2021.10.19.464936

Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain

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Abstract

Filament assembly of amyloid-{beta} peptides ending at residue 42 (A{beta}42) is a central event in Alzheimers disease. We report the cryo-EM structures of A{beta}42 filaments from brain. 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 Alzheimers disease and Type II filaments in individuals with familial Alzheimers disease and other conditions. The structures of A{beta}42 filaments from brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, A{beta}42 deposits were made of Type II filaments. Knowledge of A{beta}42 filament structures from human brain may lead to the development of inhibitors of assembly and improved imaging agents.

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Yang, Y. `, Arseni, D., Zhang, W., Huang, M., Lövestam, S., Schweighauser, M., Kotecha, A., Murzin, A. G., Peak-Chew, S. Y., Macdonald, J., Lavenir, I., Garringer, H. J., Gelpi, E., Newell, K. L., Kovacs, G. G., Vidal, R., Ghetti, B., Falcon, B., Scheres, S., Goedert, M.. 2021-10-19. Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain. https://doi.org/10.1101/2021.10.19.464936

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