Capturing a Reactive State of Amyloid Aggregates

Parthasarathy, Sudhakar; Yoo, Byong Kwon; McElheny, Dan; Tay, William M.; Ishii, Yoshitaka

doi:10.1074/jbc.m113.511345

Cited by 45 publications

(26 citation statements)

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“…It was generally proposed that production of H 2 O 2 from O 2 occurs directly via a2-electron process without any release of O 2 C À (Scheme 1, mechanism 2). [9,14,18,23,24] This seems coherent, because considering the redox potentials at neutral pH the electron reduction from O 2 to H 2 O 2 is ad own-hill reaction (exergonic), in contrast to the endergonic one-electron reduction of O 2 to O 2 C À .C omputational chemistry supported that Cu I -Ab can activate O 2 to form O 2 C À , [25,26] and that no O 2 C À is released during the H 2 O 2 production (O 2 C À was proposed as an intermediate bound to Cu-Ab). [26] Here,w eu se an electrochemical setup and the specificity of superoxide dismutase-1 (SOD1) to show that the H 2 O 2 production of Cu-Ab proceeds mainly via free O 2 C À as intermediate.T he impact of these findings on ROS production therapeutic approaches in AD is discussed.…”

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confidence: 83%

“…[21,22] In contrast to the well supported production of H 2 O 2 and HOC,d etection of O 2 C À by nitro blue tetrazolium (NBT) or hydroethidine failed. [9,14,18,23,24] This seems coherent, because considering the redox potentials at neutral pH the electron reduction from O 2 to H 2 O 2 is ad own-hill reaction (exergonic), in contrast to the endergonic one-electron reduction of O 2 to O 2 C À .C omputational chemistry supported that Cu I -Ab can activate O 2 to form O 2 C À , [25,26] and that no O 2 C À is released during the H 2 O 2 production (O 2 C À was proposed as an intermediate bound to Cu-Ab). [9,14,18,23,24] This seems coherent, because considering the redox potentials at neutral pH the electron reduction from O 2 to H 2 O 2 is ad own-hill reaction (exergonic), in contrast to the endergonic one-electron reduction of O 2 to O 2 C À .C omputational chemistry supported that Cu I -Ab can activate O 2 to form O 2 C À , [25,26] and that no O 2 C À is released during the H 2 O 2 production (O 2 C À was proposed as an intermediate bound to Cu-Ab).…”

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confidence: 99%

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Free Superoxide is an Intermediate in the Production of H₂O₂ by Copper(I)‐Aβ Peptide and O₂

et al. 2015

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Oxidative stress is considered as an important factor and an early event in the etiology of Alzheimer's disease (AD). Cu bound to the peptide amyloid-β (Aβ) is found in AD brains, and Cu-Aβ could contribute to this oxidative stress, as it is able to produce in vitro H2O2 and HO˙ in the presence of oxygen and biological reducing agents such as ascorbate. The mechanism of Cu-Aβ-catalyzed H2O2 production is however not known, although it was proposed that H2O2 is directly formed from O2 via a 2-electron process. Here, we implement an electrochemical setup and use the specificity of superoxide dismutase-1 (SOD1) to show, for the first time, that H2O2 production by Cu-Aβ in the presence of ascorbate occurs mainly via a free O2˙(-) intermediate. This finding radically changes the view on the catalytic mechanism of H2O2 production by Cu-Aβ, and opens the possibility that Cu-Aβ-catalyzed O2˙(-) contributes to oxidative stress in AD, and hence may be of interest.

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confidence: 83%

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confidence: 99%

Free Superoxide is an Intermediate in the Production of H₂O₂ by Copper(I)‐Aβ Peptide and O₂

et al. 2015

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“…93 Two binding sites were identified: the Met35 mediating the Fenton reaction through the electron donor sulfide group; 94 and the N-terminal region forming a chelating domain 95 of Asp1, His6, His13 and His14, which undergoes a major structural rearrangement during the redox cycle of ROS production. 96 Interestingly, in vitro experiments have also shown that metal binding noticeably extends the lag time by stabilizing oligomeric and amorphous aggregates, 97 which may explain the poor in vivo detection of the peptide amyloids. Aβ-copper complexes have also been shown to promote lipid peroxidation, in particular within the polyunsaturated chains of membrane lipids, which is another potential toxic mechanism due to neuronal membrane disruption.…”

Section: Aβ Tau and Alzheimer’s Diseasementioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

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“…H 2 O 2 may react with another reduced metal ion to produce toxic HO radicals through Fenton reaction (Fig. 64 Metal binding elongates the lag phase of fibril formation or stabilizes the oligomeric state. 59 These radical species are said to be involved in lipid and protein peroxidation and finally leading to neuronal death.…”

Section: Oxidative Stressmentioning

confidence: 99%

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

2015

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Amyloidogenesis has been implicated in a broad spectrum of diseases in which amyloid protein is invariably misfolded and deposited in cells and organs. Alzheimer's disease is one of the most devastating ailments among amyloidogenesis induced dementia. The amyloid beta (Aβ) peptide derived from amyloid precursor protein (APP) is misfolded and deposited as plaques in the brain, which are said to be the hallmark of Alzheimer's disease. In normal brains physiological concentration of the Aβ peptide has been indicated to be involved in modulating neurogenesis and synaptic plasticity. However, excess Aβ production, its aggregation and deposition deleteriously affect a large number of biologically important pathways leading to neuronal cell death. Targeting Aβ production, Aβ aggregation or its clearance from the brain has been an active area of research for preventing or curing AD. Our Feature Article intends to detail the aggregation mechanism, the physiological role of the Aβ peptide, elaborate its toxic effects, and outline the different classes of molecules designed in the last two years to inhibit amyloidogenic APP processing, Aβ oligomerization or fibrillogenesis and to modulate different pathways for active clearance of Aβ from the brain.

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Capturing a Reactive State of Amyloid Aggregates

Abstract: Background: Association of redox-active Cu 2ϩ with aggregated A␤ in amyloid plaques has been linked with ROS and oxidative stress in AD. Results: Cu 2ϩ /Cu ϩ -bound A␤ fibrils undergo a redox cycle reaction with ascorbate and oxygen to produce H 2 O 2 .

Cited by 45 publications

References 91 publications

Free Superoxide is an Intermediate in the Production of H₂O₂ by Copper(I)‐Aβ Peptide and O₂

Free Superoxide is an Intermediate in the Production of H₂O₂ by Copper(I)‐Aβ Peptide and O₂

Implications of peptide assemblies in amyloid diseases

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

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Capturing a Reactive State of Amyloid Aggregates

Abstract: Background: Association of redox-active Cu 2ϩ with aggregated A␤ in amyloid plaques has been linked with ROS and oxidative stress in AD. Results: Cu 2ϩ /Cu ϩ -bound A␤ fibrils undergo a redox cycle reaction with ascorbate and oxygen to produce H 2 O 2 .

Cited by 45 publications

References 91 publications

Free Superoxide is an Intermediate in the Production of H2O2 by Copper(I)‐Aβ Peptide and O2

Free Superoxide is an Intermediate in the Production of H2O2 by Copper(I)‐Aβ Peptide and O2

Implications of peptide assemblies in amyloid diseases

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Contact Info

Product

Resources

About

Free Superoxide is an Intermediate in the Production of H₂O₂ by Copper(I)‐Aβ Peptide and O₂

Free Superoxide is an Intermediate in the Production of H₂O₂ by Copper(I)‐Aβ Peptide and O₂