Alzheimer Aβ amyloid tubular fibrils: Insight into polymorphism

Elucidating the structure of Aβ 40 /Aβ 42 fibrils is of interest in Alzheimer's disease research because it is required for designing therapeutics that target fibril formation at an early stage of the disease. Based on the cryoEM measurements and on ssNMR data, we probe various amyloid fibril organizations. Our study demonstrates that the two‐fold symmetry tubular Aβ 42 fibril model with the C‐termini facing the external surface of the fibril has a cavity, while model with the C‐termini facing the internal surface of the fibril shrinks the tubular cavity. Experimentally, data for the three‐fold symmetry structure of the Aβ 9–40 fibril suggest formation of tight hydrophobic core through M35 interactions across the fibril axis and strong I31‐V39 interactions between different cross‐β units. Herein, based on ssNMR data, we probe various models with three‐fold symmetry of the full‐length Aβ 40 . We revealed that the unique Aβ 40 triangular structure has a large cavity along the fibril axis. Finally, the N‐termini in Aβ 40 /Aβ 42 fibrils can assist in the stabilization of the fibril by interacting with the U‐turn domains or with the C‐termini domains. Our findings point to the relevance of the cavity in oligomers which should be considered, when targeting oligomer toxicity. This project has been funded in whole or in part with Federal funds from the NCI, NIH, under contract number HHSN261200800001E.