Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-β peptide

Faller, Peter; Hureau, Christelle

doi:10.1039/b813398k

Cited by 494 publications

(735 citation statements)

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“…The pM values represent the metal binding affinity of L2-b at a specific pH value as well as an estimate of its ability to sequester metal ions bound to Aβ peptide (21,35). The pCu and pZn values for L2-b, corresponding to approximate dissociation constants (K d ), indicated that these K d values were comparable to the reported ones of Cu-Aβ (picomolar to nanomolar) and Zn-Aβ (micromolar) (2,3,8,9,21,(35)(36)(37). Thus, the affinities of L2-b for Cu 2þ and Zn 2þ at the relevant pHs [for metal-induced Aβ aggregation (2-4, 7-9)] suggest that this compound is able to chelate metal ions from soluble Aβ species, which could support the results from reactivity studies of L2-b with metal-treated Aβ species (vide infra).…”

Section: Resultssupporting

confidence: 49%

“…In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1)(2)(3)(4)(6)(7)(8)(9)(10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13).…”

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confidence: 99%

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Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

256

420

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The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N 1 ,N 1 -dimethyl-N 4 -(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.amyloid-β peptide | copper | zinc | reactive oxygen species | rational structure-based design M ore than 24 million people worldwide have Alzheimer's disease (AD), a devastating and fatal form of dementia (1-3). The key pathological markers in AD are amyloid-β (Aβ) plaques and neurofibrillary tangles, the accumulation of which is accompanied by oxidative stress, inflammation, and neurodegeneration. The "amyloid hypothesis" in AD states that Aβ, generated via cleavage of the amyloid precursor protein (APP) by β-and γ-secretases, is a proximal causative agent (1-4). It is, however, still unclear which morphological Aβ species, from soluble small oligomers to large fibrils, are central to AD pathogenesis (1-5).In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1-4, 6-10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13). The role of metal ions in AD and molecular mechanisms of metal-Aβ-associated pathological pathways, however, are not fully understood. Using traditional metal chelating agents, potential regulation of metal-induced Aβ aggregation and neurotoxicity has been shown in vitro and in vivo (1-4, 6, 10, 13-17). Some compounds such as clioquinol (CQ) and an 8-hydroxyquinoline derivative (PBT2) have moved into clinical trials and showed improved cognition. Long-term use of CQ is, however, limited by an adverse side effect, subacute myelo-optic neuropathy (18). Although these traditional metal chelators have yet to be available as therapeutic agents, the studies using these compounds show the possible involvement of metal ions in AD pathogenesis.To elucidate the pathological ...

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Section: Resultssupporting

confidence: 49%

mentioning

confidence: 99%

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

256

420

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“…The 39 or 42 residue polypeptide consists of a largely hydrophilic N-terminal domain , containing the metal binding site, and a C-terminal hydrophobic domain (29-40∕42). This peptide can bind one equivalent of Cu II ions with high affinity (6,7). Most of the Cu II coordination studies have been performed on the truncated Aβ16 (DAEFRHDSG YEVHHQK) peptide (see structure in SI Appendix) that was shown to be a valuable model of Cu II binding sites and affinity (6,(8)(9)(10).…”

mentioning

confidence: 99%

“…Most of the Cu II coordination studies have been performed on the truncated Aβ16 (DAEFRHDSG YEVHHQK) peptide (see structure in SI Appendix) that was shown to be a valuable model of Cu II binding sites and affinity (6,(8)(9)(10). At physiological pH, two Cu II (Aβ) complexes coexist (7,10,11); the predominant form at physiological pH is pure near pH 6.7, whereas the minor form is pure near pH 8.9 (12,13). The former complex exhibits a distorted square planar geometry with a 3N1O equatorial coordination mode where the −NH 2 terminus, two imidazole rings of His6 and His13 or His14, and an oxygen atom, the attribution of which is still debated, are the ligands deduced from pulsed-EPR studies on 13 C and 15 N-labeled peptides (13)(14)(15)(16).…”

mentioning

confidence: 99%

Electrochemical and homogeneous electron transfers to the Alzheimer amyloid-β copper complex follow a preorganization mechanism

Balland

Hureau

Savéant

2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

116

177

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Deciphering the electron transfer reactivity characteristics of amyloid β-peptide copper complexes is an important task in connection with the role they are assumed to play in Alzheimer’s disease. A systematic analysis of this question with the example of the amyloid β-peptide copper complex by means of its electrochemical current–potential responses and of its homogenous reactions with electrogenerated fast electron exchanging osmium complexes revealed a quite peculiar mechanism: The reaction proceeds through a small fraction of the complex molecules in which the peptide complex is “preorganized” so as the distances and angles in the coordination sphere to vary minimally upon electron transfer, thus involving a remarkably small reorganization energy (0.3 eV). This preorganization mechanism and its consequences on the reactivity should be taken into account for reactions involving dioxygen and hydrogen peroxide that are considered to be important in Alzheimer’s disease through the production of harmful reactive oxygen species.

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“…6,7 Several in vitro studies have related the formation of the deposits and the observed toxicity to the interaction of Aβ with these metal cations. [8][9][10][11][12][13][14] In this sense, copper has been the most intensively studied [15][16][17][18][19][20][21][22] because of its abundance in the cerebral medium and its high redox activity. In particular, several studies have focused in the determination of the copper coordination center at different pH values by means of continuous wave electron paramagnetic resonance (CW-EPR) and hyperfine sublevel correlation (HYSCORE) spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

Modeling Cu2+-Aβ complexes from computational approaches

et al. 2015

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Amyloid plaques formation and oxidative stress are two key events in the pathology of the Alzheimer disease (AD), in which metal cations have been shown to play an important role. In particular, the interaction of the redox active Cu2+ metal cation with Aβ has been found to interfere in amyloid aggregation and to lead to reactive oxygen species (ROS). A detailed knowledge of the electronic and molecular structure of Cu2+-Aβ complexes is thus important to get a better understanding of the role of these complexes in the development and progression of the AD disease. The computational treatment of these systems requires a combination of several available computational methodologies, because two fundamental aspects have to be addressed: the metal coordination sphere and the conformation adopted by the peptide upon copper binding. In this paper we review the main computational strategies used to deal with the Cu2+-Aβ coordination and build plausible Cu2+-Aβ models that will afterwards allow determining physicochemical properties of interest, such as their redox potential.

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Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-β peptide

Cited by 494 publications

References 130 publications

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Electrochemical and homogeneous electron transfers to the Alzheimer amyloid-β copper complex follow a preorganization mechanism

Modeling Cu2+-Aβ complexes from computational approaches

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