Dataset Information

A Trishistidine Pseudopeptide with Ability to Remove Both Cu? and Cu?? from the Amyloid-? Peptide and to Stop the Associated ROS Formation.

ABSTRACT: The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (A?). Its synthesis and coordination properties for Cu? and Cu?? are described. L efficiently complex Cu?? in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, Cu? is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the Cu? complex to oxidation by oxygen and the Cu?? complex reduction by ascorbate. The affinities of L for Cu?? and Cu? at physiological pH are larger than that reported for the A? peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuA? complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease.

SUBMITTER: Conte-Daban A

PROVIDER: S-EPMC5714062 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

A Trishistidine Pseudopeptide with Ability to Remove Both CuΙ and CuΙΙ from the Amyloid-β Peptide and to Stop the Associated ROS Formation.

Conte-Daban Amandine A Boff Bastien B Candido Matias Andreza A Aparicio Claudia N Montes CNM Gateau Christelle C Lebrun Colette C Cerchiaro Giselle G Kieffer Isabelle I Sayen Stéphanie S Guillon Emmanuel E Delangle Pascale P Hureau Christelle C

Chemistry (Weinheim an der Bergstrasse, Germany) 20171109 67

The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for CuΙ and CuΙΙ are described. L efficiently complex CuΙΙ in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, CuΙ is coordinated in a tetrahedral enviro ...[more]

PMID: 28846165

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Project description:Amyloid β peptide oligomers (AβOs), toxic aggregates with pivotal roles in Alzheimer's disease, trigger persistent and low magnitude Ca2+ signals in neurons. We reported previously that these Ca2+ signals, which arise from Ca2+ entry and subsequent amplification by Ca2+ release through ryanodine receptor (RyR) channels, promote mitochondrial network fragmentation and reduce RyR2 expression. Here, we examined if AβOs, by inducing redox sensitive RyR-mediated Ca2+ release, stimulate mitochondrial Ca2+-uptake, ROS generation and mitochondrial fragmentation, and also investigated the effects of the antioxidant N-acetyl cysteine (NAC) and the mitochondrial antioxidant EUK-134 on AβOs-induced mitochondrial dysfunction. In addition, we studied the contribution of the RyR2 isoform to AβOs-induced Ca2+ release, mitochondrial Ca2+ uptake and fragmentation. We show here that inhibition of NADPH oxidase type-2 prevented the emergence of RyR-mediated cytoplasmic Ca2+ signals induced by AβOs in primary hippocampal neurons. Treatment with AβOs promoted mitochondrial Ca2+ uptake and increased mitochondrial superoxide and hydrogen peroxide levels; ryanodine, at concentrations that suppress RyR activity, prevented these responses. The antioxidants NAC and EUK-134 impeded the mitochondrial ROS increase induced by AβOs. Additionally, EUK-134 prevented the mitochondrial fragmentation induced by AβOs, as previously reported for NAC and ryanodine. These findings show that both antioxidants, NAC and EUK-134, prevented the Ca2+-mediated noxious effects of AβOs on mitochondrial function. Our results also indicate that Ca2+ release mediated by the RyR2 isoform causes the deleterious effects of AβOs on mitochondrial function. Knockdown of RyR2 with antisense oligonucleotides reduced by about 50% RyR2 mRNA and protein levels in primary hippocampal neurons, decreased by 40% Ca2+ release induced by the RyR agonist 4-chloro-m-cresol, and significantly reduced the cytoplasmic and mitochondrial Ca2+ signals and the mitochondrial fragmentation induced by AβOs. Based on our results, we propose that AβOs-induced Ca2+ entry and ROS generation jointly stimulate RyR2 activity, causing mitochondrial Ca2+ overload and fragmentation in a feed forward injurious cycle. The present novel findings highlight the specific participation of RyR2-mediated Ca2+ release on AβOs-induced mitochondrial malfunction.

Dataset Information

A Trishistidine Pseudopeptide with Ability to Remove Both Cu? and Cu?? from the Amyloid-? Peptide and to Stop the Associated ROS Formation.

Publications

A Trishistidine Pseudopeptide with Ability to Remove Both Cu<sup>Ι</sup> and Cu<sup>ΙΙ</sup> from the Amyloid-β Peptide and to Stop the Associated ROS Formation.

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