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Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Aβ) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Aβ(1–40), starting from monomeric Aβ to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel β-sheet. These structural changes are described in terms of H-bonding rupture/formation, β-strands reorientation and β-sheet elongation. As antiparallel β-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the β-sheet implicating a reorientation of β-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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Abbreviations

Aβ:

Amyloid-beta

AD:

Alzheimer’s disease

ADDLs:

Aβ-derived diffusible ligands

AFM:

Atomic force microscopy

ATR:

Attenuated total reflection

DMSO:

Dimethylsulfoxide

FTIR:

Fourier-transform infrared spectroscopy

TBS:

Tris-buffered saline solution

ThT:

Thioflavin T

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Acknowledgments

R.S. is Research Fellow for the Fund for Research in the Industry and Agriculture (Belgium), E.C. is Research Fellow for the National Fund for Scientific Research (Belgium), Y.F.D. and V.R. are Senior Research Associate and E.G. is Research Director for the National Fund for Scientific Research (Belgium). We thank Dr. C. Glabe for kindly providing A11 antibody, Dr. P. Boussard and Dr. Y. Looze for access to the fluorimeter.

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Authors and Affiliations

  1. Laboratory for Structure and Function of Biological Membranes, Faculté des Sciences, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles, CP 206/2, Blvd. du Triomphe, 1050, Brussels, Belgium

    Rabia Sarroukh, Emilie Cerf, Erik Goormaghtigh, Jean-Marie Ruysschaert & Vincent Raussens

  2. Unité de Chimie des Interfaces, Université Catholique de Louvain, Croix du Sud 2/18, 1348, Louvain-la-Neuve, Belgium

    Sylvie Derclaye & Yves F. Dufrêne

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  1. Rabia Sarroukh
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  2. Emilie Cerf
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Correspondence to Jean-Marie Ruysschaert.

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R. Sarroukh and E. Cerf have equally contributed to this work.

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Sarroukh, R., Cerf, E., Derclaye, S. et al. Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure. Cell. Mol. Life Sci. 68, 1429–1438 (2011). https://doi.org/10.1007/s00018-010-0529-x

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