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

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 Cu(2+) 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 Cu(2+) 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, Cu(2+) 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 Cu(2+) 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 Cu(2+) binding on these two aggregation pathways in terms of charge and structural variations.

SUBMITTER: Jiang D

PROVIDER: S-EPMC3464049 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Jiang Dianlu D Rauda Iris I Han Shubo S Chen Shu S Zhou Feimeng F

Langmuir : the ACS journal of surfaces and colloids 20120822 35

Amyloid β (Aβ) fibrils are present as a major component in senile plaques, the hallmark of Alzheimer's disease (AD). Diffuse plaques (nonfibrous, loosely packed Aβ aggregates) containing amorphous Aβ aggregates are also formed in brain. This work examines the influence of Cu(2+) complexation by Aβ on the aggregation process in the context of charge and structural variations. Changes in the surface charges of Aβ molecules due to Cu(2+) binding, measured with a ζ-potential measurement device, were ...[more]

PMID: 22870885

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Project description:Amyloid fibrils are associated with many neurodegenerative diseases. It was found that amyloidogenic oligomers, not mature fibrils, are neurotoxic agents related to these diseases. Molecular mechanisms of infectivity, pathways of aggregation, and molecular structure of these oligomers remain elusive. Here, we use all-atom molecular dynamics, molecular mechanics combined with solvation analysis by statistical-mechanical, three-dimensional molecular theory of solvation (also known as 3D-RISM-KH) in a new MM-3D-RISM-KH method to study conformational stability, and association thermodynamics of small wild-type Abeta(17-42) oligomers with different protonation states of Glu(22), as well the E22Q (Dutch) mutants. The association free energy of small beta-sheet oligomers shows near-linear trend with the dimers being thermodynamically more stable relative to the larger constructs. The linear (within statistical uncertainty) dependence of the association free energy on complex size is a consequence of the unilateral stacking of monomers in the beta-sheet oligomers. The charge reduction of the wild-type Abeta(17-42) oligomers upon protonation of the solvent-exposed Glu(22) at acidic conditions results in lowering the association free energy compared to the wild-type oligomers at neutral pH and the E22Q mutants. The neutralization of the peptides because of the E22Q mutation only marginally affects the association free energy, with the reduction of the direct electrostatic interactions mostly compensated by the unfavorable electrostatic solvation effects. For the wild-type oligomers at acidic conditions such compensation is not complete, and the electrostatic interactions, along with the gas-phase nonpolar energetic and the overall entropic effects, contribute to the lowering of the association free energy. The differences in the association thermodynamics between the wild-type Abeta(17-42) oligomers at neutral pH and the Dutch mutants, on the one hand, and the Abeta(17-42) oligomers with protonated Glu(22), on the other, may be explained by destabilization of the inter- and intrapeptide salt bridges between Asp(23) and Lys(28). Peculiarities in the conformational stability and the association thermodynamics for the different models of the Abeta(17-42) oligomers are rationalized based on the analysis of the local physical interactions and the microscopic solvation structure.

Dataset Information

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

Publications

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

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