Copper-mediated Amyloid-β Toxicity Is Associated with an Intermolecular Histidine Bridge

Smith, David P.; Smith, D.G.; Curtain, Cyril C.; Boas, John F.; Pilbrow, John R.; Ciccotosto, Giuseppe D.; Lau, Tong-Lay; Tew, Deborah J.; Perez, Keyla; Wade, John D.; Bush, Ashley I.; Drew, Simon C.; Separovic, Frances; Masters, Colin L.; Cappai, Roberto; Barnham, Kevin J.

doi:10.1074/jbc.m600417200

Cited by 174 publications

(200 citation statements)

References 46 publications

(90 reference statements)

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“…The coexistence of both the amyloid material and the Cu 2+ induced aggregates would suggest two mutually exclusive aggregation pathways. At Cu 2+ :peptide ratios of ∼0.3:1 and above, the A peptide has been shown to form a histidine-bridged Cu 2+ dimer, as observed by EPR, which is essential for the metal mediated toxic effect and the formation of this bridge appears to corresponds with the initial formation of the Cu 2+ induced aggregates (17,19,44). However, variant peptide in which the formation of the His bridge was ablated still formed Cu 2+ induced aggregates; hence, Cu 2+ induced aggregation of A is not dependent on the ability of the peptide to form a His bridge but on its ability to coordinate the initial Cu 2+ (17).…”

Section: Implications For the Aggregation Of A Peptidementioning

confidence: 90%

“…We have previously demonstrated that unaged A 1-42 at a Cu 2+ :peptide molar ratio of 1:1 and 1:10 is highly neurotoxic and this toxicity correlated with the formation of a histidine bridged dimer (17). Unaged A 1-42 at a Cu 2+ :peptide molar ratios 0:1 and 0.1:1 also showed neurotoxic activity; however, this effect was diminished in comparison to the 1:1 and 10:1 molar ratios (17). It is unknown, however, what effect aging has on the neurotoxic activity of Cu 2+ induced aggregates.…”

Section: Cu 2+ :Peptide Molar Ratio Controls the Aggregation State Ofmentioning

confidence: 99%

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Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

et al. 2007

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The Amyloid peptide (A ) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline associated with the disease. Cu 2+ ions can induce the de noVo aggregation of the A peptide into non-amyloidogenic aggregates and the production of a toxic species. The mechanism by which Cu 2+ mediates the change from amyloid material toward Cu 2+ induced aggregates is poorly defined. Here we demonstrate that the aggregation state of A 1-42 at neutral pH is governed by the Cu 2+ :peptide molar ratio. By probing amyloid content and total aggregation, we observed a distinct Cu 2+ switching effect centered at equimolar Cu 2+ :peptide ratios. At sub-equimolar Cu 2+ :peptide molar ratios, A 1-42 forms thioflavin-T reactive amyloid; conversely, at supra-equimolar Cu 2+ :peptide molar ratios, A 1-42 forms both small spherical oligomers approximately 10-20 nm in size and large amorphous aggregates. We demonstrate that these insoluble aggregates form spontaneously via a soluble species without the presence of an observable lag phase. In seeding experiments, the Cu 2+ induced aggregates were unable to influence fibril formation or convert into fibrillar material. Aged Cu 2+ induced aggregates are toxic when compared to A 1-42 aged in the absence of Cu 2+ . Importantly, the formation of dityrosine crosslinked A , by the oxidative modification of the peptide, only occurs at equimolar molar ratios and above. The formation of dityrosine adducts occurs following the initiation of aggregation and hence does not drive the formation of the Cu 2+ induced aggregates. These results define the role Cu 2+ plays in modulating the aggregation state and toxicity of A 1-42.

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Section: Implications For the Aggregation Of A Peptidementioning

confidence: 90%

Section: Cu 2+ :Peptide Molar Ratio Controls the Aggregation State Ofmentioning

confidence: 99%

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

et al. 2007

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“…Manipulations of the amino acids in A , including His imidazole N-methylation, have been conducted to learn more about the redox control of Cu coordination and the role of particular side chains in ROS generation and neurotoxicity (170)(171)(172)(173)(174)(175)(176)(177)(178). At the same time, however, other studies have found evidence for a ROS detoxication role of A (100).…”

Section: Role Of Oxidative Stress In Admentioning

confidence: 99%

Oxidative Stress and Neurotoxicity

Sayre

Perry

Smith

2007

Chem. Res. Toxicol.

725

483

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There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.

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“…Metal ions, including copper, iron, and zinc, bind to Aβ both in vitro and within Aβ plaques from the brains of AD patients (28,29). In in vitro assembly reactions with Aβ, the addition of copper favors the formation of nonfibrillar, amorphous aggregates (29) and oligomers (30,31) that are more toxic to cells than amyloid fibers of Aβ (18,(30)(31)(32). Metal binding compounds, such as CQ and PBT2, can remove metals from Aβ in vitro (17,18,33,34).…”

Section: Screen For Compounds That Rescue Aβ Toxicity In Yeastmentioning

confidence: 99%

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

Matlack

Tardiff

Narayan

et al. 2014

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

152

136

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Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-β peptide (Aβ) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by Aβ has been hindered by a lack of cellular models amenable to high-throughput chemical screening. To address this gap, we use a robust and scalable yeast model of Aβ toxicity where the Aβ peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic Aβ 1-42 peptide forms more oligomers and is more toxic than Aβ 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of ∼140,000 compounds for rescue of Aβ toxicity. Of ∼30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce Aβ burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of Aβ secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced Aβ peptide levels in a copper-dependent manner by increasing degradation, ultimately restoring endocytic function. This mirrored its effects on copper-dependent oligomer formation in vitro, which was also reversed by CQ. This unbiased screen indicates that copper-dependent Aβ oligomer formation contributes to Aβ toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the Aβ yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.phenotypic small-molecule screen | metal chelation A lzheimer's disease (AD) is a common and devastating neurodegenerative disorder that is projected to increase in frequency as our population ages. The lack of disease-modifying therapies requires new approaches to address the underlying mechanisms of cellular dysfunction and identify potential therapeutics.The amyloid-β peptide (Aβ) plays a major role in AD and ultimately leads to neuronal death and cognitive impairment (1). Aβ peptides of ∼40 aa are generated by the successive cleavage of the amyloid precursor protein (APP) by β-and γ-secretases. Mutations in APP or γ-secretase cause familial AD and bias APP cleavage toward a 42-aa Aβ peptide that predominates in Aβ plaques, is more aggregation prone, and is toxic to neurons (2, 3). Although Aβ plaques are a common, conspicuous feature of pathology in diseased brains, increasing evidence suggests that small oligomers of Aβ are the most toxic species (4, 5).

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Copper-mediated Amyloid-β Toxicity Is Associated with an Intermolecular Histidine Bridge

Cited by 174 publications

References 46 publications

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

Oxidative Stress and Neurotoxicity

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

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Copper-mediated Amyloid-β Toxicity Is Associated with an Intermolecular Histidine Bridge

Cited by 174 publications

References 46 publications

Concentration Dependent Cu2+Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

Concentration Dependent Cu2+Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

Oxidative Stress and Neurotoxicity

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

Contact Info

Product

Resources

About

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

Concentration Dependent Cu²⁺Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide