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  • 1
    Language: English
    In: The journal of physical chemistry. B, 15 December 2011, Vol.115(49), pp.14812-21
    Description: Alzheimer's disease is a neurodegenerative disorder in which the formation of amyloid-β (Aβ) aggregates plays a causative role. There is ample evidence that Cu(II) can bind to Aβ and modulate its aggregation. Moreover, Cu(II) bound to Aβ might be involved in the production of reactive oxygen species, a process supposed to be involved in the Alzheimer's disease. The native Aβ40 contains a high affinity binding site for Cu(II), which is comprised in the N-terminal portion. Thus, Aβ16 (amino acid 1-16 of Aβ) has often been used as a model for Cu(II)-binding to monomeric Aβ. The Cu(II)-binding to Aβ is pH dependent and at pH 7.4, two different type of Cu(II) coordinations exist in equilibrium. These two forms are predominant at pH 6.5 and pH 9.0. In either form, a variety of studies show that the N-terminal Asp and the three His play a key role in the coordination, although the exact binding of these amino acids has not been addressed. Therefore, we studied the coordination modes of Cu(II) at pH 6.5 and 9.0 with the help of Fourier transform infrared (FTIR) spectroscopy. Combined with isotopic labeling of the amino acids involved in the coordination sphere, the data points toward the coordination of Cu(II) via the carboxylate of Asp1 at both pH values in a pseudobridging monovalent fashion. At low pH, His6 binds copper via Nτ, while His13 and His14 are bound via Nπ. At high pH, direct evidence is given on the coordination of Cu(II) via the Nτ atom of His6. Additionally, this study clearly shows the effect of Cu(II) binding on the protonation state of the His residues where a proton displacement takes places on the nitrogen atoms of the imidazole ring.
    Keywords: Amyloid Beta-Peptides -- Chemistry ; Copper -- Chemistry ; Peptide Fragments -- Chemistry
    ISSN: 15206106
    E-ISSN: 1520-5207
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  • 2
    Language: English
    In: Journal of Applied Physics, Nov 15, 2012, Vol.112(10), p.103506-1-103506-7
    Description: Numerous analyses are carried out for examining the impacts of high-pressure torsion (HPT) on the microstructure and free-volume type defects of supersaturated Al-3 wt%Cu. The nanocrystalline structure is shown to get stabilized by the precipitates.
    Keywords: Aluminum Alloys -- Mechanical Properties ; Aluminum Alloys -- Thermal Properties ; Deformation -- Methods ; Doppler Effect -- Usage ; Nanoparticles -- Usage ; Positron Annihilation -- Analysis
    ISSN: 0021-8979
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: The journal of physical chemistry. B, 27 December 2013, Vol.117(51), pp.16455-67
    Description: According to the amyloid cascade hypothesis, amyloid-β peptides (Aβ) play a causative role in Alzheimer's disease (AD), of which oligomeric forms are proposed to be the most neurotoxic by provoking oxidative stress. Copper ions seem to play an important role as they are bound to Aβ in amyloid plaques, a hallmark of AD. Moreover, Cu-Aβ complexes are able to catalyze the production of hydrogen peroxide and hydroxyl radicals, and oligomeric Cu-Aβ was reported to be more reactive. The flexibility of the unstructured Aβ peptide leads to the formation of a multitude of different forms of both Cu(I) and Cu(II) complexes. This raised the question of the structure-function relationship. We address this question for the biologically relevant Fenton-type reaction. Computational models for the Cu-Aβ complex in monomeric and dimeric forms were built, and their redox behavior was analyzed together with their reactivity with peroxide. A set of 16 configurations of Cu-Aβ was studied and the configurations were classified into 3 groups: (A) configurations that evolve into a linearly bound and nonreactive Cu(I) coordination; (B) reactive configurations without large reorganization between the two Cu redox states; and (C) reactive configurations with an open structure in the Cu(I)-Aβ coordination, which have high water accessibility to Cu. All the structures that showed high reactivity with H2O2 (to form HO(•)) fall into class C. This means that within all the possible configurations, only some pools are able to produce efficiently the deleterious HO(•), while the other pools are more inert. The characteristics of highly reactive configurations consist of a N-Cu(I)-N coordination with an angle far from 180° and high water crowding at the open side. This allows the side-on entrance of H2O2 and its cleavage to form a hydroxyl radical. Interestingly, the reactive Cu(I)-Aβ states originated mostly from the dimeric starting models, in agreement with the higher reactivity of oligomers. Our study gives a rationale for the Fenton-type reactivity of Cu-Aβ and how dimeric Cu-Aβ could lead to a higher reactivity. This opens a new therapeutic angle of attack against Cu-Aβ-based reactive oxygen species production.
    Keywords: Models, Molecular ; Alzheimer Disease -- Metabolism ; Amyloid Beta-Peptides -- Metabolism ; Copper -- Metabolism ; Hydrogen Peroxide -- Metabolism ; Iron -- Metabolism
    ISSN: 15206106
    E-ISSN: 1520-5207
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  • 4
    Language: English
    In: Inorganic chemistry, 04 November 2013, Vol.52(21), pp.12193-206
    Description: Aggregation of amyloid-β (Aβ) by self-assembly into oligomers or amyloids is a central event in Alzheimer's disease. Coordination of transition-metal ions, mainly copper and zinc, to Aβ occurs in vivo and modulates the aggregation process. A survey of the impact of Cu(II) and Zn(II) on the aggregation of Aβ reveals some general trends: (i) Zn(II) and Cu(II) at high micromolar concentrations and/or in a large superstoichiometric ratio compared to Aβ have a tendency to promote amorphous aggregations (precipitation) over the ordered formation of fibrillar amyloids by self-assembly; (ii) metal ions affect the kinetics of Aβ aggregations, with the most significant impact on the nucleation phase; (iii) the impact is metal-specific; (iv) Cu(II) and Zn(II) affect the concentrations and/or the types of aggregation intermediates formed; (v) the binding of metal ions changes both the structure and the charge of Aβ. The decrease in the overall charge at physiological pH increases the overall driving force for aggregation but may favor more precipitation over fibrillation, whereas the induced structural changes seem more relevant for the amyloid formation.
    Keywords: Alzheimer Disease -- Metabolism ; Amyloid Beta-Peptides -- Chemistry ; Copper -- Metabolism ; Zinc -- Metabolism
    ISSN: 00201669
    E-ISSN: 1520-510X
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  • 5
    Language: English
    In: Chemistry – A European Journal, 07 December 2012, Vol.18(50), pp.15910-15920
    Description: Metal ions Cu, Zn and Fe, seem to play a pivotal role in Alzheimer’s disease and other neurodegenerative diseases. In order to understand this in a broader sense, one has to considerer the peculiarities of metal metabolism in the brain compared to most other tissues, as well as the importance of the redox active metal ions, Fe and Cu, in oxygen metabolism and the connected oxidative stress. Vieles deutet auf eine zentral Rolle der Metallionen Cu, Zn und Fe in der Alzheimer’schen als auch in anderen neurodegenerativen Krankheiten hin. Für ein grundsätzlicheres Verständnis dafür sollten die Eigenheiten des Metalmetabolismus im Hirn bezüglich anderen Geweben in Betracht gezogen werden, sowie auch die Bedeutung der redoxaktiven Metallen im Stoffwechsel des Sauerstoffs und des damit verbundenen oxidativen Stresses. : In this Concept article the principles of the redox active metals and oxygen metabolism and their relation to Alzheimer's disease (AD) are discussed. The many questions that remain open regarding the crucial role of metal ions in AD and the perspectives for future research are highlighted.
    Keywords: Alzheimer’s Disease ; Amyloid Beta Peptides ; Bioinorganic Chemistry ; Neurochemistry ; Transition Metals
    ISSN: 0947-6539
    E-ISSN: 1521-3765
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  • 6
    Language: English
    In: Chemistry - A European Journal, 12/07/2012, Vol.18(50), pp.15889-15889
    Description: The main players concerning the role of metal ions in the neurodegenerative Alzheimer's disease (AD) are shown in this cover picture: The d orbital stands for the importance of the first‐row transition metals (mainly Cu and Fe), and the unpaired electron for the redox reactivity and the production of harmful reactive radicals. The bottom two pictures show the amyloids that contain Cu, Zn, and Fe (right) and the Cu/Fe‐catalyzed production of reactive oxygen species (left), both occurring in AD. The upper part shows two therapeutic approaches for treatment of AD based on selective intervention in the metal metabolism. For more information, see the Concept article by P. Faller and C. Hureau on page 15910 ff.
    Keywords: Chemistry;
    ISSN: Chemistry - A European Journal
    E-ISSN: 09476539
    E-ISSN: 15213765
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  • 7
    Language: English
    In: Inorganic chemistry, 03 December 2012, Vol.51(23), pp.12988-3000
    Description: Alzheimer's disease is characterized by senile plaques in which metallic ions (copper, zinc, and iron) are colocalized with amyloid-β peptides of different sequences in aggregated forms. In addition to the full-length peptides (Aβ1-40/42), N-terminally truncated Aβ3-40/42 forms and their pyroglutamate counterparts, Aβp3-40/42, have been proposed to play key features in the aggregation process, leading to the senile plaques. Furthermore, they have been shown to be more toxic than the full-length Aβ, which made them central targets for therapeutic approaches. In order to better disentangle the possible role of metallic ions in the aggregation process, copper(II) coordination to the full-length amyloid peptides has been extensively studied in the last years. However, regarding the N-terminally modified forms at position 3, very little is known. Therefore, copper(I) and copper(II) coordination to those peptides have been investigated in the present report using a variety of complementary techniques and as a function of pH. Copper(I) coordination is not affected by the N-terminal modifications. In contrast, copper(II) coordination is different from that previously reported for the full-length peptide. In the case of the pyroglutamate form, this is due to preclusion of N-terminal amine binding. In the case of the N-terminally truncated form, alteration in copper(II) coordination is caused by second-sphere effects that impact the first binding shell and the pH-dependent repartition of the various [Cu(peptide)] complexes. Such second-sphere effects are anticipated to apply to a variety of metal ions and peptides, and their importance on changing the first binding shell has not been fully recognized yet.
    Keywords: Amyloid Beta-Peptides -- Chemistry ; Copper -- Chemistry ; Organometallic Compounds -- Chemical Synthesis
    ISSN: 00201669
    E-ISSN: 1520-510X
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  • 8
    Language: English
    In: Inorganic chemistry, 02 January 2012, Vol.51(1), pp.701-8
    Description: Supramolecular assembly of peptides and proteins into amyloid fibrils is of multifold interest, going from materials science to physiopathology. The binding of metal ions to amyloidogenic peptides is associated with several amyloid diseases, and amyloids with incorporated metal ions are of interest in nanotechnology. Understanding the mechanisms of amyloid formation and the role of metal ions can improve strategies toward the prevention of this process and enable potential applications in nanotechnology. Here, studies on Zn(II) binding to the amyloidogenic peptide Aβ11-28 are reported. Zn(II) modulates the Aβ11-28 aggregation, in terms of kinetics and fibril structures. Structural studies suggest that Aβ11-28 binds Zn(II) by amino acid residues Glu11 and His14 and that Zn(II) is rapidly exchanged between peptides. Structural and aggregation data indicate that Zn(II) binding induces the formation of the dimeric Zn(II)(1)(Aβ11-28)(2) species, which is the building block of fibrillar aggregates and explains why Zn(II) binding accelerates Aβ11-28 aggregation. Moreover, transient Zn(II) binding, even briefly, was enough to promote fibril formation, but the final structure resembled that of apo-Aβ11-28 amyloids. Also, seeding experiments, i.e., the addition of fibrillar Zn(II)(1)(Aβ11-28)(2) to the apo-Aβ11-28 peptide, induced aggregation but not propagation of the Zn(II)(1)(Aβ11-28)(2)-type fibrils. This can be explained by the dynamic Zn(II) binding between soluble and aggregated Aβ11-28. As a consequence, dynamic Zn(II) binding has a strong impact on the aggregation behavior of the Aβ11-28 peptide and might be a relevant and so far little regarded parameter in other systems of metal ions and amyloidogenic peptides.
    Keywords: Amyloid -- Metabolism ; Amyloid Beta-Peptides -- Metabolism ; Peptide Fragments -- Metabolism ; Zinc -- Metabolism
    ISSN: 00201669
    E-ISSN: 1520-510X
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  • 9
    Language: English
    In: Inorganic chemistry, 19 September 2011, Vol.50(18), pp.9024-30
    Description: Iron has been implicated in Alzheimer's disease, but until now no direct proof of Fe(II) binding to the amyloid-β peptide (Aβ) has been reported. We used NMR to evidence Fe(II) coordination to full-length Aβ40 and truncated Aβ16 peptides at physiological pH and to show that the Fe(II) binding site is located in the first 16 amino-acid residues. Fe(II) caused selective broadening of some NMR peaks that was dependent on the Fe:Aβ stoichiometry and temperature. Analysis of Fe(II) broadening effect in the (1)H, (13)C, and 2D NMR data established that Asp1, Glu3, the three His, but not Tyr10 nor Met35 are the residues mainly involved in Fe(II) coordination.
    Keywords: Alzheimer Disease -- Metabolism ; Amyloid Beta-Peptides -- Metabolism ; Iron -- Metabolism
    ISSN: 00201669
    E-ISSN: 1520-510X
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  • 10
    Language: English
    In: Inorganic chemistry, 07 November 2011, Vol.50(21), pp.11192-201
    Description: Copper ions have been proposed to intervene in deleterious processes linked to the development of Alzheimer's disease (AD). As a direct consequence, delineating how Cu(II) can be bound to amyloid-β (Aβ) peptide, the amyloidogenic peptide encountered in AD, is of paramount importance. Two different forms of [Cu(II)(Aβ)] complexes are present near physiological pH, usually noted components I and II, the nature of which is still widely debated in the literature, especially for II. In the present report, the phenomenological pH-dependent study of Cu(II) coordination to Aβ and to ten mutants by EPR, CD, and NMR techniques is described. Although only indirect insights can be obtained from the study of Cu(II) binding to mutated peptides, they reveal very useful for better defining Cu(II) coordination sites in the native Aβ peptide. Four components were identified between pH 6 and 12, namely, components I, II, III and IV, in which the predominant Cu(II) equatorial sites are {-NH(2), CO (Asp1-Ala2), N(im) (His6), N(im) (His13 or His14)}, {-NH(2), N(-) (Asp1-Ala2), CO (Ala2-Glu3), N(im)}, {-NH(2), N(-) (Asp1-Ala2), N(-) (Ala2-Glu3), N(im)} and {-NH(2), N(-) (Asp1-Ala2), N(-) (Ala2-Glu3), N(-) (Glu3-Phe4)}, respectively, in line with classical pH-induced deprotonation of the peptide backbone encountered in Cu(II) peptidic complexes formation. The structure proposed for component II is discussed with respect to another coordination model reported in the literature, that is, {CO (Ala2-Glu3), 3 N(im)}. Cu(II) binding to the H6R-Aβ and D7N-Aβ peptides, where the familial H6R and D7N mutations have been linked to early onset of AD, has also been investigated. In case of the H6R mutation, some different structural features (compared to those encountered in the native [Cu(II)(Aβ)] species) have been evidenced and are anticipated to be important for the aggregating properties of the H6R-Aβ peptide in presence of Cu(II).
    Keywords: Amyloid Beta-Peptides ; Point Mutation ; Amino Acids -- Metabolism ; Copper -- Metabolism
    ISSN: 00201669
    E-ISSN: 1520-510X
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