Investigation of the Mechanism of β-Amyloid Fibril Formation by Kinetic and Thermodynamic Analyses
Resource
Langmuir 24 (11): 5802-5808
Journal
Langmuir
Journal Volume
24
Journal Issue
11
Pages
5802-5808
Date Issued
2008
Date
2008
Author(s)
Abstract
Extracellular β-amyloid (Aβ) deposit is considered as one of the primary factors that induce Alzheimer's disease (AD). The effects of various environmental factors, including temperature, ionic strength, and pH, on Aβ (1-40) aggregation mechanisms were investigated in this study by spectrometry, isothermal titration calorimetry (ITC), and hydrophobic fluorescence assay. In the aggregation process, the secondary structure of Aβ (1-40) transforms to the β-sheet conformation, which could be described as a two-state model. As the temperature and ionic strength increase, the conformation of Aβ converts to the β-sheet structure with an increased rate. Results of circular dichroism monitoring demonstrate that the rate constant of nucleation is smaller than that of elongation, and the nucleation is the rate-determining step during the overall Aβ aggregation. The β-sheet structure was stabilized by hydrophobic forces, as revealed by the ITC measurements. The different structural aggregates and forming pathways could be identified and discriminated at high and low ionic strengths, resulting in distinctive fibril conformations. Furthermore, the thermodynamic analysis shows that hydrophobic interaction is the major driving force in the nucleation step. Our study provides an insight into the discriminative mechanisms of β-amyloid aggregation via kinetics and thermodynamics, especially the first reported thermodynamics information obtained by ITC. © 2008 American Chemical Society.
Other Subjects
Agglomeration; Conformations; Deposits; Dichroism; Dynamics; Epitaxial growth; Forming; Glycoproteins; Hydrophobicity; Mechanics; Mechanisms; Microfluidics; Nucleation; Optical properties; pH; pH effects; Rate constants; Thermoanalysis; Thermodynamic properties; Thermodynamics; Volumetric analysis; (p ,p ,t) measurements; Aggregation processing; Alzheimer's disease (AD); American Chemical Society (ACS); amyloid fibril formation; Circular dichroism (DC); driving forces; Environmental factors; Extracellular; fluorescence assays; Hydrophobic (hydrophilic) force; Hydrophobic interactions; Isothermal titration calorimetry (ITC); Kinetic (Polym.); Kinetics and thermodynamics; Primary factors; Rate determining step (RDS); secondary structures; Sheet structures; Strength (IGC: D5/D6); Two state models; Ionic strength; amyloid; amyloid beta protein; amyloid beta protein[1-40]; peptide fragment; animal; article; chemistry; heat; human; hydrophobicity; kinetics; pH; protein quaternary structure; protein secondary structure; Amyloid; Amyloid beta-Protein; Animals; Heat; Humans; Hydrogen-Ion Concentration; Hydrophobicity; Kinetics; Peptide Fragments; Protein Structure, Quaternary; Protein Structure, Secondary
Type
journal article
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