caa a22 4500 606176276 CHVBK 20210128100746.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s00018-015-1983-2 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1983-2 Two distinct β-sheet structures in Italian-mutant amyloid-beta fibrils: a potential link to different clinical phenotypes [Elektronische Daten] [Ellen Hubin, Stéphanie Deroo, Gabriele Schierle, Clemens Kaminski, Louise Serpell, Vinod Subramaniam, Nico van Nuland, Kerensa Broersen, Vincent Raussens, Rabia Sarroukh] Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development of early-onset familial AD. This type of AD is associated with a younger age at disease onset, increased β-amyloid accumulation, and Aβ deposition in cerebral blood vessel walls, giving rise to cerebral amyloid angiopathy (CAA). It remains largely unknown how the Italian mutation results in the clinical phenotype that is characteristic of CAA. We therefore investigated how this single point mutation may affect the aggregation of Aβ1-42 in vitro and structurally characterized the resulting fibrils using a biophysical approach. This paper reports that wild-type and Italian-mutant Aβ both form fibrils characterized by the cross-β architecture, but with distinct β-sheet organizations, resulting in differences in thioflavin T fluorescence and solvent accessibility. E22K Aβ1-42 oligomers and fibrils both display an antiparallel β-sheet structure, in comparison with the parallel β-sheet structure of wild-type fibrils, characteristic of most amyloid fibrils described in the literature. Moreover, we demonstrate structural plasticity for Italian-mutant Aβ fibrils in a pH-dependent manner, in terms of their underlying β-sheet arrangement. These findings are of interest in the ongoing debate that (1) antiparallel β-sheet structure might represent a signature for toxicity, which could explain the higher toxicity reported for the Italian mutant, and that (2) fibril polymorphism might underlie differences in disease pathology and clinical manifestation. The Author(s), 2015 Amyloid-beta peptide nationallicence E22K mutation nationallicence Secondary structure nationallicence Fibril polymorphism nationallicence Tropism nationallicence β-sheet conformation nationallicence AD : Alzheimer's disease nationallicence AFM : Atomic force microscopy nationallicence ATR : Attenuated total reflectance nationallicence Aβ : Amyloid-beta peptide nationallicence CAA : Cerebral amyloid angiopathy nationallicence DMSO : Dimethyl sulfoxide nationallicence ESI : Electrospray ionization nationallicence FAD : Familial Alzheimer's disease nationallicence FTIR : Fourier transform infrared nationallicence HDX : Hydrogen/deuterium exchange nationallicence HFIP : Hexafluoroisopropanol nationallicence MS : Mass spectrometry nationallicence NMR : Nuclear magnetic resonance nationallicence TBS : Tris-buffered saline nationallicence TEM : Transmission electron microscopy nationallicence ThT : Thioflavin T nationallicence WT : Wild type nationallicence Hubin Ellen Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands aut Deroo Stéphanie Laboratory of Structure and Function of Biological Membrane, Faculté des Sciences, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles (ULB), Campus de la Plaine CP 206/02, Boulevard du Triomphe, 1050, Brussels, Belgium aut Schierle Gabriele Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, CB2 3RA, Cambridge, UK aut Kaminski Clemens Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, CB2 3RA, Cambridge, UK aut Serpell Louise School of Life Sciences, University of Sussex, Falmer, BN1 9QG, East Sussex, UK aut Subramaniam Vinod Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands aut van Nuland Nico Structural Biology Brussels, Department of Biotechnology (DBIT), Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050, Brussels, Belgium aut Broersen Kerensa Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands aut Raussens Vincent Laboratory of Structure and Function of Biological Membrane, Faculté des Sciences, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles (ULB), Campus de la Plaine CP 206/02, Boulevard du Triomphe, 1050, Brussels, Belgium aut Sarroukh Rabia Laboratory of Structure and Function of Biological Membrane, Faculté des Sciences, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles (ULB), Campus de la Plaine CP 206/02, Boulevard du Triomphe, 1050, Brussels, Belgium aut Cellular and Molecular Life Sciences Springer International Publishing 72/24(2015-12-01), 4899-4913 1420-682X 72:24<4899 2015 72 18 https://doi.org/10.1007/s00018-015-1983-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1983-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hubin Ellen Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands aut NATIONALLICENCE 700 1- Deroo Stéphanie Laboratory of Structure and Function of Biological Membrane, Faculté des Sciences, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles (ULB), Campus de la Plaine CP 206/02, Boulevard du Triomphe, 1050, Brussels, Belgium aut NATIONALLICENCE 700 1- Schierle Gabriele Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, CB2 3RA, Cambridge, UK aut NATIONALLICENCE 700 1- Kaminski Clemens Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, CB2 3RA, Cambridge, UK aut NATIONALLICENCE 700 1- Serpell Louise School of Life Sciences, University of Sussex, Falmer, BN1 9QG, East Sussex, UK aut NATIONALLICENCE 700 1- Subramaniam Vinod Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands aut NATIONALLICENCE 700 1- van Nuland Nico Structural Biology Brussels, Department of Biotechnology (DBIT), Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050, Brussels, Belgium aut NATIONALLICENCE 700 1- Broersen Kerensa Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands aut NATIONALLICENCE 700 1- Raussens Vincent Laboratory of Structure and Function of Biological Membrane, Faculté des Sciences, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles (ULB), Campus de la Plaine CP 206/02, Boulevard du Triomphe, 1050, Brussels, Belgium aut NATIONALLICENCE 700 1- Sarroukh Rabia Laboratory of Structure and Function of Biological Membrane, Faculté des Sciences, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles (ULB), Campus de la Plaine CP 206/02, Boulevard du Triomphe, 1050, Brussels, Belgium aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer International Publishing 72/24(2015-12-01), 4899-4913 1420-682X 72:24<4899 2015 72 18