Dataset Information

Conformational Ensembles of the Wild-Type and S8C A?1-42 Dimers.

ABSTRACT: We characterized the dimer of the amyloid-? wild-type (WT) peptide, A?, of 42 residues and its disulfide-bond-locked double mutant (S8C) by replica exchange molecular dynamics simulations. A? dimers are known to be the smallest toxic species in Alzheimer's disease, and the S8C mutant has been shown experimentally to form an exclusive homogeneous and neurotoxic dimer. Our 50 ?s all-atom simulations reveal similar secondary structures and collision cross-sections but very different intramolecular and intermolecular conformations upon double S8C mutation. Both dimers are very dynamic with hundreds of free-energy minima that differ from the U-shape and S-shape conformations of the peptides in the fibrils. The only common structural feature, shared by both species with a probability of 4% in WT and 12% in S8C-S8C, is a three-stranded ?-sheet spanning the 17-23, 29-36, and 39-41 residues, which does not exist in the A?40 WT dimers.

SUBMITTER: Man VH

PROVIDER: S-EPMC5944329 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Conformational Ensembles of the Wild-Type and S8C Aβ1-42 Dimers.

Man Viet Hoang VH Nguyen Phuong H PH Derreumaux Philippe P

The journal of physical chemistry. B 20170310 11

We characterized the dimer of the amyloid-β wild-type (WT) peptide, Aβ, of 42 residues and its disulfide-bond-locked double mutant (S8C) by replica exchange molecular dynamics simulations. Aβ dimers are known to be the smallest toxic species in Alzheimer's disease, and the S8C mutant has been shown experimentally to form an exclusive homogeneous and neurotoxic dimer. Our 50 μs all-atom simulations reveal similar secondary structures and collision cross-sections but very different intramolecular ...[more]

PMID: 28245647

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Project description:Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer's disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of amyloid beta (Aβ) peptides from the brain. Correspondingly, in patients suffering from AD, defects in the capacity of peripheral macrophages to engulf Aβ have been reported. The effects of carnosine on macrophages and oxidative stress associated with AD are consequently of substantial interest for drug discovery in this field. In the present work, a model of stress induced by Aβ1-42 oligomers was investigated using a combination of methods including trypan blue exclusion, microchip electrophoresis with laser-induced fluorescence, flow cytometry, fluorescence microscopy, and high-throughput quantitative real-time PCR. These assays were used to assess the ability of carnosine to protect macrophage cells, modulate oxidative stress, and profile the expression of genes related to inflammation and pro- and antioxidant systems. We found that pre-treatment of RAW 264.7 macrophages with carnosine counteracted cell death and apoptosis induced by Aβ1-42 oligomers by decreasing oxidative stress as measured by levels of intracellular nitric oxide (NO)/reactive oxygen species (ROS) and production of peroxynitrite. This protective activity of carnosine was not mediated by modulation of the canonical inflammatory pathway but instead can be explained by the well-known antioxidant and free-radical scavenging activities of carnosine, enhanced macrophage phagocytic activity, and the rescue of fractalkine receptor CX3CR1. These new findings obtained with macrophages challenged with Aβ1-42 oligomers, along with the well-known multimodal mechanism of action of carnosine in vitro and in vivo, substantiate the therapeutic potential of this dipeptide in the context of AD pathology.

Dataset Information

Conformational Ensembles of the Wild-Type and S8C A?1-42 Dimers.

Publications

Conformational Ensembles of the Wild-Type and S8C Aβ1-42 Dimers.

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