Copper in the brain and Alzheimer’s disease

Hung, Ya Hui; Bush, Ashley I.; Cherny, Robert A.

doi:10.1007/s00775-009-0600-y

Cited by 433 publications

(231 citation statements)

References 266 publications

Supporting

Mentioning

224

Contrasting

Unclassified

Order By: Relevance

“…The H6R mutation facilitates zinc‐induced dimerisation of the N terminus;25 however, here we focus exclusively on copper, as it has much stronger interactions with Aβ 26. Furthermore, its interactions with wild‐type Aβ (wt‐Aβ) has been linked with an increase in oligomerisation/fibrillisation, as well as being a source of oxidative damage 27. The coordination environment of copper bound to Aβ has been solved by EPR for both wt‐Aβ and mutants H6R and D7N 28, 29.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

et al. 2016

View full text Add to dashboard Cite

Mutations and post‐translational modifications of amyloid‐β (Aβ) peptide in its N terminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two Aβ peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with Aβ peptide phosphorylated at serine 8 (pS8). All three peptides bind to copper with a similar rate as the wild‐type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50 % faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper‐bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of Aβ.

show abstract

Section: Introductionmentioning

confidence: 99%

Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

et al. 2016

View full text Add to dashboard Cite

show abstract

“…It has been described that deposition of misfolded proteins increases the amount of ROS [37], by causing inflammation in neuroglia, which, in turn, catalyzes ROS formation [38,39]. Aβ, αS, and PrP also complex metal ions, such as FeII and CuI, that strongly catalyze ROS formation [40,41]. Concentrations of CuI and FeII are in amyloid plaques are about twice as high as in surrounding tissues [42].…”

Section: Toxicity and Amyloid Formationmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

View full text Add to dashboard Cite

Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Copper in the brain and Alzheimer’s disease

Cited by 433 publications

References 266 publications

Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Modeling Cu2+-Aβ complexes from computational approaches

Contact Info

Product

Resources

About