title: Thioflavin T templates amyloid β(1-40) conformation and aggregation pathway.
abstract: Aβ(1-40) peptide supramolecular assembly and fibril formation processes are widely recognized to have direct implications in the progression of Alzheimer's disease. The molecular basis of this biological process is still unknown and there is a strong need of developing effective strategies to control the occurring events. To this purpose the exploitation of small molecules interacting with Aβ aggregation represents one of the possible routes. Moreover, the use specific labeling has represented so far one of the most common and effective methods to investigate such a process. This possibility in turn rests on the reliability of the probe/labels involved. Here we present evidences of the effect of Thioflavin T (ThT), a worldwide used fluorescent dye to monitor amyloid growth, on the Aβ(1-40) conformation, stability and aggregation. By combining experimental information and Molecular Dynamics simulation results, we show that the presence of ThT in solution affects peptide conformation inducing peculiar supramolecular association. In particular ThT interactions with specific Aβ(1-40) residues promote a rigid partially-folded conformation which shifts the balance between different species in solution toward a more aggregation-prone ensemble of peptides, leading to aggregation. Our findings suggest ways for developing strategies to reverse and block aggregation or to stimulate supramolecular assembly and consequently reduce the presence of transient oligomers. This investigation underlines the need of developing label-free techniques for unbiased quantitative studies of Aβ(1-40) aggregation processes.
authors.affiliation: Dipartimento di Fisica e Chimica, Università degli Studi di Palermo, Via Archirafi 36, I-90123 Palermo, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Di Carlo
authors.affiliation: Dipartimento di Fisica, Università degli Studi di Roma "Tor Vergata", Via della Ricerca Scientifica 1, I-00133 Roma, Italy; INFN, Italy. Electronic address: minicozzi@roma2.infn.it.
authors.forename: Velia
authors.initials: V
authors.lastname: Minicozzi
authors.affiliation: Section for Biologics, Department of Pharmacy, University of Copenhagen, Univeristetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: vito.fodera@sund.ku.dk.
authors.forename: Vito
authors.initials: V
authors.lastname: Foderà
authors.affiliation: Dipartimento di Fisica e Chimica, Università degli Studi di Palermo, Via Archirafi 36, I-90123 Palermo, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Militello
authors.affiliation: Dipartimento di Fisica e Chimica, Università degli Studi di Palermo, Via Archirafi 36, I-90123 Palermo, Italy. Electronic address: valeria.vetri@unipa.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Vetri
authors.affiliation: Dipartimento di Fisica, Università degli Studi di Roma "Tor Vergata", Via della Ricerca Scientifica 1, I-00133 Roma, Italy; INFN, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morante
authors.affiliation: Dipartimento di Fisica e Chimica, Università degli Studi di Palermo, Via Archirafi 36, I-90123 Palermo, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Leone
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D052160:Benzothiazoles; D036681:Fluorescence Recovery After Photobleaching; D005456:Fluorescent Dyes / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D013844:Thiazoles / Q000032:analysis / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D066329:Protein Aggregates; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T
keywords: Alzheimer's disease; Aβ(1–40) peptide; Protein aggregation; Protein conformation; Secondary structure; Thioflavin T