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An N-heterocyclic amine chelate capable of antioxidant capacity and amyloid disaggregation.

ABSTRACT: Alzheimer's disease is a neurodegenerative disorder characterized by the development of intracellular neurofibrillary tangles, deposition of extracellular amyloid beta (A?) plaques, along with a disruption of transition metal ion homeostasis in conjunction with oxidative stress. Spectroscopic, transmission electron microscopy, and scanning electron microscopy imaging studies show that 1 (pyclen) is capable of both preventing and disrupting Cu(2+) induced AB(1-40) aggregation. The pyridine backbone of 1 engenders antioxidant capacity, as shown by cellular DCFH-DA (dichlorodihydrofluorescein diacetate) assay in comparison to other N-heterocyclic amines lacking this aromatic feature. Finally, 1 prevents cell death induced by oxidative stress as shown by the Calcein AM assay. The results are supported using density functional theory studies which show that the pyridine backbone is responsible for the antioxidant capacity observed.

SUBMITTER: Lincoln KM

PROVIDER: S-EPMC3503443 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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An N-heterocyclic amine chelate capable of antioxidant capacity and amyloid disaggregation.

Lincoln Kimberly M KM Richardson Timothy E TE Rutter Lauren L Gonzalez Paulina P Simpkins James W JW Green Kayla N KN

ACS chemical neuroscience 20120831 11

Alzheimer's disease is a neurodegenerative disorder characterized by the development of intracellular neurofibrillary tangles, deposition of extracellular amyloid beta (Aβ) plaques, along with a disruption of transition metal ion homeostasis in conjunction with oxidative stress. Spectroscopic, transmission electron microscopy, and scanning electron microscopy imaging studies show that 1 (pyclen) is capable of both preventing and disrupting Cu(2+) induced AB(1-40) aggregation. The pyridine backbo ...[more]

PMID: 23173072

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Project description:Amyloidlike fibrils are found in many fatal diseases, including Alzheimer's disease, type II diabetes mellitus, transmissible spongiform encephalopathies, and prion diseases. These diseases are linked to proteins that have partially unfolded, misfolded, and aggregated into amyloidlike fibrils. The kinetics of amyloidlike fibrils aggregation is still hotly debated and remains an important open question. We have utilized the GNNQQNY crystal structure and high-temperature molecular dynamics simulation in explicit solvent to study the disaggregation mechanism of the GNNQQNY fibrils and to infer its likely aggregation pathways. A hexamer model and a 12-mer model both with two parallel beta-sheets separated by a dry side-chain interface were adopted in our computational analysis. A cumulative time of 1 micros was simulated for the hexamer model at five different temperatures (298 K, 348 K, 398 K, 448 K, and 498 K), and a cumulative time of 2.1 micros was simulated for the 12-mer model at four temperatures (298 K, 398 K, 448 K, and 498 K). Our disaggregation landscape and kinetics analyses indicate that tetramers probably act as the transition state in both the hexamer and the 12-mer simulations. In addition, the 12-mer simulations show that the initial aggregation nucleus is with eight peptides. Furthermore, the landscape is rather flat from 8-mers to 12-mers, indicating the absence of major barriers once the initial aggregation nucleus forms. Thus, the likely aggregation pathway is from monomers to the initial nucleus of 8-mers with tetramers as the transition state. Transition state structure analysis shows that the two dominant transition state conformations are tetramers in the 3-1 and 2-2 arrangements. The predominant nucleus conformations are in peptide arrangements maximizing dry side-chain contacts. Landscape and kinetics analyses also indicate that the parallel beta-sheets form earlier than the dry side-chain contacts during aggregation. These results provide further insights in understanding the early fibrils aggregation.

Dataset Information

An N-heterocyclic amine chelate capable of antioxidant capacity and amyloid disaggregation.

Publications

An N-heterocyclic amine chelate capable of antioxidant capacity and amyloid disaggregation.

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