The effect of Aβ conformation on the metal affinity and aggregation mechanism studied by circular dichroism spectroscopy

The conformational change and associated aggregation of β amyloid (Aβ) with or without metals is the main cause of Alzheimers' disease (AD). In order to further understand the effects of Aβ and its associated metals on the aggregation mechanism, the influence of Aβ conformation on the metal affinity and aggregation was investigated using circular dichroism (CD) spectroscopy. The Aβ conformation is dependent on pH and trifluoroethanol (TFE). The binding of metals to Aβ was found to be dependent on the Aβ conformation. The aggregation induced by Aβ itself or its associated metals is completely diminished for Aβ in 40% TFE. Only in 5% and 25% TFE can Aβ undergo an α-helix to β-sheet aggregation, which involve a three-state mechanism for the metal-free state, and a two-state transition for the metal-bound state, respectively. The aggregation-inducing activity of metals is in the order, Cu²⁺ > Fe³⁺ ≥ Al ³⁺ > Zn²⁺.