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Investigation of the mechanism of beta-amyloid fibril formation by kinetic and thermodynamic analyses.

Lin MS, Chen LY, Tsai HT, Wang SS, Chang Y, Higuchi A, Chen WY

Department of Chemical and Materials Engineering, National Central University, Jhong-Li, Taiwan 320.

Extracellular beta-amyloid (A beta) 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 A beta (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 A beta (1-40) transforms to the beta-sheet conformation, which could be described as a two-state model. As the temperature and ionic strength increase, the conformation of A beta converts to the beta-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 A beta aggregation. The beta-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 beta-amyloid aggregation via kinetics and thermodynamics, especially the first reported thermodynamics information obtained by ITC.

Published 28 May 2008 in Langmuir, 24(11): 5802-8.
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