title: Two distinct β-sheet structures in Italian-mutant amyloid-beta fibrils: a potential link to different clinical phenotypes.
abstract: 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.
authors.affiliation: Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands.|Structural Biology Brussels, Department of Biotechnology (DBIT), Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050, Brussels, Belgium.|Structural Biology Research Center, VIB, Pleinlaan 2, 1050, Brussels, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hubin
authors.affiliation: 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.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Deroo
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge, CB2 3RA, UK.
authors.forename: Gabriele Kaminksi
authors.initials: GK
authors.lastname: Schierle
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge, CB2 3RA, UK.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kaminski
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, East Sussex, BN1 9QG, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Serpell
authors.affiliation: Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands.|FOM Institute AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Subramaniam
authors.affiliation: Structural Biology Brussels, Department of Biotechnology (DBIT), Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050, Brussels, Belgium.|Structural Biology Research Center, VIB, Pleinlaan 2, 1050, Brussels, Belgium.
authors.forename: Nico
authors.initials: N
authors.lastname: van Nuland
authors.affiliation: Nanobiophysics Group, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands. k.broersen@utwente.nl.
authors.forename: Kerensa
authors.initials: K
authors.lastname: Broersen
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Raussens
authors.affiliation: 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. rsarrouk@ulb.ac.be.
authors.forename: Rabia
authors.initials: R
authors.lastname: Sarroukh
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D010641:Phenotype; D017354:Point Mutation; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides
keywords: Amyloid-beta peptide; E22K mutation; Fibril polymorphism; Secondary structure; Tropism; β-sheet conformation