Aggregation Pathways of the Amyloid β(1-42) Peptide Depend on Its Colloidal Stability and Ordered β-Sheet Stacking

Amyloid beta (A beta) fibrils are present as a major component in senile plaques, the hallmark of Alzheimer's disease (AD). Diffuse plaques (nonfibrous, loosely packed A beta aggregates) containing amorphous A beta aggregates are also formed in brain. This work examines the influence of Cu2+ complexation by A beta on the aggregation process in the context of charge and structural variations. Changes in the surface charges of A beta molecules due to Cu2+ binding, measured with a zeta-potential measurement device, were correlated with the aggregate morphologies examined by atomic force microscopy. As a result of the charge variation, the colloid-like stability of the aggregation intermediates, which is essential to the fibrillation process, is affected. Consequently, Cu2+ enhances the amorphous aggregate formation. By monitoring variations in the secondary structures with circular dichroism spectroscopy, a direct transformation from the unstructured conformation to the beta-sheet structure was observed for all types of aggregates observed (oligomers, fibrils, and/or amorphous aggregates). Compared to the A beta aggregation pathway in the absence of Cu2+ and taking other factors affecting A beta aggregation (i.e., pH and temperature) into account, our investigation indicates that formations of amorphous and fibrous aggregates diverge from the same beta-sheet-containing partially folded intermediate. This study suggests that the hydrophilic domain of A beta also plays a role in the A beta aggregation process. A kinetic model was proposed to account for the effects of the Cu2+ binding on these two aggregation pathways in terms of charge and structural variations.