TY - JOUR

T1 - Thioflavin T templates amyloid β(1-40) conformation and aggregation pathway

AU - Di Carlo, Maria Giovanna

AU - Minicozzi, Velia

AU - Foderà, Vito

AU - Militello, Valeria

AU - Vetri, Valeria

AU - Morante, Silvia

AU - Leone, Maurizio

N1 - Copyright © 2015 Elsevier B.V. All rights reserved.

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - Alzheimer Disease

KW - Amino Acid Sequence

KW - Amyloid beta-Peptides

KW - Fluorescence Recovery After Photobleaching

KW - Fluorescent Dyes

KW - Humans

KW - Molecular Dynamics Simulation

KW - Molecular Sequence Data

KW - Peptide Fragments

KW - Protein Aggregates

KW - Protein Aggregation, Pathological

KW - Protein Conformation

KW - Protein Multimerization

KW - Protein Stability

KW - Protein Structure, Secondary

KW - Thiazoles

U2 - 10.1016/j.bpc.2015.06.006

DO - 10.1016/j.bpc.2015.06.006

M3 - Journal article

C2 - 26100600

VL - 206

SP - 1

EP - 11

JO - Biophysical Chemistry

JF - Biophysical Chemistry

SN - 0301-4622

ER -