The Unique Alzheimer’s β-Amyloid Triangular Fibril Has a Cavity along the Fibril Axis under Physiological Conditions

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Abstract
Elucidating the structure of Aβ1−40 fibrils is of interest in Alzheimer’s disease research because it is required for designing therapeutics that target Aβ1−40 fibril formation at an early stage of the disease. M35 is a crucial residue because of its potential oxidation and its strong interactions across β-strands and across β-sheets in Aβ fibrils. Experimentally, data for the three-fold symmetry structure of the Aβ9−40 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, on the basis of experimental data, we probe conformers with three-fold symmetry of the full-length Aβ1−40. Our all-atom molecular dynamics simulations in explicit solvent of conformers based on the ssNMR data reproduced experimental observations of M35−M35 and I31−V39 distances. Our interpretation of the experimental data suggests that the observed ∼5−7 Å M35−M35 distance in the fibril three-fold symmetry structure is likely to relate to M35 interactions along the fibril axis, rather than across the fibril axis, since our measured M35−M35 distances across the fibril axis are consistently above 15 Å. Consequently, we revealed that the unique Aβ1−40 triangular structure has a large cavity along the fibril axis and that the N-termini can assist in the stabilization of the fibril by interacting with the U-turn domains or with the C-termini domains. Our findings, together with the recent cyroEM characterization of the hollow core in Aβ1−42 fibrils, point to the relevance of a cavity in Aβ1−40/1−42 oligomers which should be considered when targeting oligomer toxicity.