Aggregation pathways of the amyloid ?(1 42) peptide depend on its colloidal stability and ordered ?-sheet stacking

Document Type

Article

Publication Date

9-4-2012

Abstract

Amyloid ? (A?) fibrils are present as a major component in senile plaques, the hallmark of Alzheimer's disease (AD). Diffuse plaques (nonfibrous, loosely packed A? aggregates) containing amorphous A? aggregates are also formed in brain. This work examines the influence of Cu2+ complexation by A? on the aggregation process in the context of charge and structural variations. Changes in the surface charges of A? molecules due to Cu2+ binding, measured with a ?-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 ?-sheet structure was observed for all types of aggregates observed (oligomers, fibrils, and/or amorphous aggregates). Compared to the A? aggregation pathway in the absence of Cu2+ and taking other factors affecting A? aggregation (i.e., pH and temperature) into account, our investigation indicates that formations of amorphous and fibrous aggregates diverge from the same ?-sheet-containing partially folded intermediate. This study suggests that the hydrophilic domain of A? also plays a role in the A? 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. © 2012 American Chemical Society.

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