Cu(II) Binding to Monomeric, Oligomeric, and Fibrillar Forms of the Alzheimer’s Disease Amyloid-β Peptide

Karr, Jesse W.; Szalai, Veronika A.

doi:10.1021/bi702423h

Cited by 111 publications

(162 citation statements)

References 81 publications

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“…In particular, the loss of main-chain amide coordination to be replaced by side-chain coordination from a histidine imidazole of a second A␤ molecule is likely to cause a profound change in the appearance of the CD bands, which is not observed. The ability of amyloid fibers to accommodate Cu binding has also been observed for A␤ and A␤ (35,(73)(74)(75)(76). Interestingly, Cu 2ϩ can diffuse into and load on to all A␤ molecules within the fibers and facilitate the Cu 2ϩ coordination with close to 1:1 stoichiometry.…”

Section: Discussionmentioning

confidence: 87%

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

Barritt

Viles

2015

Journal of Biological Chemistry

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Background: N-terminally truncated A␤ (11-40/42) typically constitutes 19% of plaque load in Alzheimer patients. Results: Cu 2ϩ binds to A␤ with a 34-fM dissociation constant and stabilizes very short highly amyloidogenic amyloid rods into longer A␤ fibers. Concussion: The very tight affinity explains the high levels of Cu 2ϩ in amyloid plaques. Significance: Copper, tightly bound to A␤ (11-40/42) , may influence disease pathology.

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Section: Discussionmentioning

confidence: 87%

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

Barritt

Viles

2015

Journal of Biological Chemistry

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“…This may be due to the very different coordination geometry (at micromolar concentration) between the two metal ions. Cu 2ϩ ions form an intramolecular complex with A␤ (25)(26)(27)(28) whereas at micromolar levels current data suggest that Zn 2ϩ will form an intermolecular complex, cross-linking between histidine residues on multiple A␤ molecules (34, 36, 49, 56). These crosslinked Zn 2ϩ -A␤ species will inhibit amyloids forming by interfering with the regular cross-beta assembly.…”

Section: Coppermentioning

confidence: 94%

“…At M concentrations of A␤, Cu 2ϩ does not form crossed-linked species (26,27,50), and the Cu 2ϩ coordination geometry is identical in the monomer and fiber (25,28). This rules out copper bridging to form cross-linked A␤ as a possible mechanism of accelerated fiber formation.…”

Section: Coppermentioning

confidence: 97%

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

Sarell

Wilkinson

Viles

2010

Journal of Biological Chemistry

181

218

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A role for Cu 2؉ ions in Alzheimer disease is often disputed, as it is believed that Cu 2؉ ions only promote nontoxic amorphous aggregates of amyloid-␤ (A␤). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu 2؉ ions in fact doubles the rate of production of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu 2؉ ions at a physiological pH causes A␤ to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu 2؉ ions bound to A␤ are consistently more toxic to neuronal cells than A␤ in the absence of Cu 2؉ ions, whereas Cu 2؉ ions in the absence of A␤ are not cytotoxic. The degree of Cu-A␤ cytotoxicity correlates with the levels of Cu 2؉ ions that accelerate fiber formation. We note the effect appears to be specific for Cu 2؉ ions as Zn 2؉ ions inhibit the formation of fibers. An active role for Cu 2؉ ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease. Alzheimer disease (AD)2 is characterized by extracellular amyloid plaques, composed predominantly of fibrillar amyloid-␤ peptide (A␤), a 39 -43-residue peptide. Genetic alterations underlying familial AD are associated with mutations or increased production of A␤, indicating that A␤ plays a central role in the disease (1).A notable characteristic of AD is altered metal ion concentrations in the brain and disrupted metal ion homeostasis (2). Cu 2ϩ ions are found concentrated within senile plaques of AD patients directly bound to A␤ (3-5). Recent in vivo studies using a Drosophila model of AD have shown that impaired copper homeostasis enhances the toxic effects of A␤ (6). Furthermore, copper in a cholesterol high diet induces amyloid plaques and learning deficits in a rabbit model of AD (7). Other in vivo studies have shown that copper homeostasis can influence AD pathology. In contrast to the Drosophila model, transgenic mice have shown a reduced AD pathology with increased intracellular copper levels (8 -10).Although studies of A␤ neurotoxicity suggest that small diffusible oligomers, rather than mature amyloid fibers, are the more toxic form (11, 12), there remains strong evidence suggesting that amyloid plaques, or possibly intermediates of the fibrils, are critical in neuronal toxicity (13,14). A␤ oligomers may be precursors of fiber formation and may also arise from fiber fragmentation. Alternatively, oligomers may be in competition with fiber formation. Both possibilities require the self-association of monomeric A␤, and thus factors that affect fibrillization will also influence oligomer generation.The mechanism by which A␤ is toxic is hotly debated (11, 15). It has been proposed that A␤ can form ion channels or pores or can thin the membrane, all of which will cause membrane leakage and loss of cellular Ca 2ϩ ion homeostasis. One popular hypothesis is that the membrane integrity is compromised by lipid peroxida...

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“…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). 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).…”

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.

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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Cu(II) Binding to Monomeric, Oligomeric, and Fibrillar Forms of the Alzheimer’s Disease Amyloid-β Peptide

Cited by 111 publications

References 81 publications

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

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

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