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Rationally designed peptoids modulate aggregation of amyloid-beta 40.

ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. Plaques composed of aggregated amyloid-beta protein (Aβ) accumulate between the neural cells in the brain and are associated with dementia and cellular death. Many strategies have been investigated to prevent Aβ self-assembly into disease-associated β-sheet amyloid aggregates; however, a promising therapeutic has not yet been identified. In this study, a peptoid-based mimic of the peptide KLVFF (residues 16-20 of Aβ) was tested for its ability to modulate Aβ aggregation. Peptoid JPT1 includes chiral, aromatic side chains to induce formation of a stable helical secondary structure that allows for greater interaction between the aromatic side chains and the cross β-sheet of Aβ. JPT1 was found to modulate Aβ40 aggregation, specifically decreasing lag time to β-sheet aggregate formation as well as the total number of fibrillar, β-sheet structured aggregates formed. These results suggest that peptoids may be able to limit the formation of Aβ aggregates that are associated with AD.

SUBMITTER: Turner JP

PROVIDER: S-EPMC4102963 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Rationally designed peptoids modulate aggregation of amyloid-beta 40.

Turner J Phillip JP Lutz-Rechtin Tammy T Moore Kelly A KA Rogers Lauren L Bhave Omkar O Moss Melissa A MA Servoss Shannon L SL

ACS chemical neuroscience 20140416 7

Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. Plaques composed of aggregated amyloid-beta protein (Aβ) accumulate between the neural cells in the brain and are associated with dementia and cellular death. Many strategies have been investigated to prevent Aβ self-assembly into disease-associated β-sheet amyloid aggregates; however, a promising therapeutic has not yet been identified. In this study, a peptoid-based mimic of ...[more]

PMID: 24689364

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Project description:Some polyphenols, which are common natural compounds in fruits, vegetables, seeds, and oils, have been considered as potent inhibitors of amyloid beta (Aβ) aggregation, one critical pathogenic event in Alzheimer's disease (AD). However, the mechanisms by which polyphenols affect aggregation are not fully understood. In this study, we aimed to investigate the effect of two classes of polyphenols (flavonoids and stilbenes) on the self-assembly of Aβ_42, in particular, how this relates to structure. We found that the flavonoids gallocatechin gallate (GCG) and theaflavin (TF) could completely inhibit Aβ aggregation, while two stilbenes, resveratrol and its glucoside derivative piceid, could also suppress Aβ aggregation, but to a much lesser extent. Intriguingly, resveratrol accelerated the formation of Aβ fibrils before its decreasing effect on fibrillation was detected. Atomic force microscopy (AFM) images showed a huge mass of long and thin Aβ fibrils formed in the presence of resveratrol. Although the morphology was the same in the presence of piceid, the fibrils were sparse in the presence of picead. In the presence of flavonoids, Aβ morphology was unchanged from prior to incubation (0 h), in agreement with amyloid beta kinetics analysis using thioflavin-T fluorescence assay. The electrochemical data showed a higher ability of GCG and TF to interact with Aβ than resveratrol and piceid, which could be attributed to the presence of more aromatic rings and hydroxyl groups. In addition, the two flavonoids exhibited a similar propensity for Aβ aggregation, despite having some differences in their structure. However, in the case of stilbenes, the addition of a glucoside at C-7 slightly decreased anti-Aβ aggregation property compared to resveratrol. These findings contribute to a better understanding of the essential structural features of polyphenols required for inhibiting Aβ aggregation, and the possible mechanisms for modulating aggregation.

Dataset Information

Rationally designed peptoids modulate aggregation of amyloid-beta 40.

Publications

Rationally designed peptoids modulate aggregation of amyloid-beta 40.

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