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bioRxiv · 10.1101/2023.10.05.561069

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

Yang, Y.·Murzin, A. G.·Peak-Chew, S.·Franco, C.·Newell, K. L.·Ghetti, B.·Goedert, M.·Scheres, S. H.
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Abstract

We used electron cryo-microscopy (cryo-EM) to determine the structures of A{beta}40 filaments from the leptomeninges of individuals with Alzheimers disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 [A], we found three types of filaments. However, our new structures, solved to a resolution of 2.4 [A] resolution, revealed differences in the sequence assignment that redefine the fold of A{beta}40 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 A{beta}42 and blood vessel deposits of A{beta}40 have distinct structures, supporting the view that Alzheimers disease and cerebral amyloid angiopathy are different A{beta} proteinopathies.

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Yang, Y., Murzin, A. G., Peak-Chew, S., Franco, C., Newell, K. L., Ghetti, B., Goedert, M., Scheres, S. H.. 2023-10-07. Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. https://doi.org/10.1101/2023.10.05.561069

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