Metallo‐ROS in Alzheimer's Disease: Oxidation of Neurotransmitters by Cu<sup>II</sup>‐β‐Amyloid and Neuropathology of the Disease

da Silva, Giordano F. Z.; Ming, Li‐June

doi:10.1002/ange.200604421

Cited by 14 publications

(20 citation statements)

References 64 publications

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“…Thus, the pro-oxidant activity of Aβ ultimately leads to its own covalent modification and accelerated amyloidogenesis. It should be noted that catecholamines can also be oxidized by Aβ:Cu complexes 21,50,51…”

Section: Metallochemistry Mediates the Aggregation And Neurotoxicimentioning

confidence: 99%

Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis

2008

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SUMMARY Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral β-amyloid deposits; e.g., senile plaques. Both ionic zinc and copper are able to accelerate the aggregation of Aβ, the principle component of β-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Aβ and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Aβ together with ionic zinc and copper in cortical glutamatergic synapses following excitation. This, in turn, leads to the formation of Aβ oligomers, which, in turn, modulate long-term potentiation (by controlling synaptic levels of the NMDA receptor). The excessive accumulation of Aβ oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmisson. Based on these findings, we have proposed the “Metal Hypothesis of Alzheimer’s Disease” which stipulates that the neuropathogenic effects of Aβ in AD are promoted by, and possibly even dependent upon Aβ-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Aβ-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Aβ–metal interactions, e.g. PBT2, are currently advancing through clinical trials and show increasing promise as disease-modifying agents for AD based on the “metal hypothesis”.

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Section: Metallochemistry Mediates the Aggregation And Neurotoxicimentioning

confidence: 99%

Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis

2008

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“…Some AD treatment strategies have targeted the metal center in metallo-A to prevent peptide aggregation and ROS generation [25][26][27][28] and the role of the metal therein was proposed [29,30]. However, comparatively little effort has been focused on the mechanism for the metal-centered chemistry, besides the production of H 2 O 2 , which as well as the reactivity of the "metallo-ROS" center [31] in CuA may contribute to the oxidative stress suspected to take place in AD [1][2][3][4][5]. Nevertheless, there are still debates on different views about the role of metalloamyloids even very recently [32].…”

Section: Accepted Manuscript I Introductionmentioning

confidence: 99%

“…Since A activity and aggregation in AD brains is sequence-specific and metal-dependent [7,8], it is a priority to establish the targets of redox activity that can contribute to the physiological and cognitive effects of AD. We have recently established that the Cu II complexes of A and its soluble fragments (A 1-16 and A 1-20 ) showed considerable activities toward the oxidation of phenol, polyphenol, catechol, and their derivatives to form o-quinones via a type-3 copper-centered mechanism [31,37,38]. Such reactivities can explain the mechanism for the formation of dityrosine in A [39] via activation of the phenol side chain and also challenge the redox role of Met35 that is not present in the fragments.…”

Section: Accepted Manuscript I Introductionmentioning

confidence: 99%

Methionine does not reduce Cu(II)–β-amyloid!—Rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)–β-amyloid

Silva

Lykourinou

Angerhofer

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The potential risk of metal-centered oxidative catalysis has been overlooked in the research of the copper complexes of the Alzheimer's disease-related beta-amyloid (Abeta) peptides. Cu(2+) complexes of Abeta(1-40) and its 1-16 and 1-20 fragments have recently been shown to exhibit significant metal-centered oxidative activities toward several catecholamine neurotransmitters with and without H(2)O(2) around neutral pH [G.F.Z. da Silva, L.-J. Ming, "Metallo-ROS" in Alzheimer's disease: metal-centered oxidation of neurotransmitters by Cu(II)-beta-amyloid and neuropathology of Alzheimer's disease, Angew. Chem. Int. Ed. 46 (2007) 3337-3341]. The results further support the metallo-Abeta-associated oxidative stress theory often considered to be connected to the neuropathology of the disease. The metal-centered oxidative catalysis of CuAbeta(1-16/20) challenges the long-standing proposed redox role of Met35 in Abeta because Abeta(1-16/20) do not contain a Met. External Met has been determined by kinetic, optical, and electron paramagnetic resonance methods to bind directly to the Cu(2+) center of CuAbeta(1-40) and CuAbeta(1-20) with K(d)=2.8 mM and 11.3 microM, respectively, which reflects less accessibility of the metal center in the full-length CuAbeta(1-40). However, Met does not serve as a reducing agent for the Cu(II) which thus must amplify the observed oxidative catalysis of CuAbeta(1-20)through a non-redox mechanism. Conversely, the CuAbeta-catalyzed oxidation reaction of dopamine is inhibited by bio-available reducing agents such as ascorbate (competitive K(ic)=66 microM) and glutathione (non-competitive, K(inc)=53 microM). These data indicate that the oxidation chemistry of metallo-Abeta is not initiated by Met35. The results yield further molecular and mechanistic insights into the roles of metallo-Abeta in this disease.

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“…The overall yield of both isomers was 35 %. 3 (1 equiv., 0.1 mmol, 0.032 g) and KOtBu (1 equiv., 0.1 mmol, 0.011 g) were mixed in a Schlenk flask under argon. To the mixture was added dry THF (10 mL), and it was stirred at room temperature for 12 h. The violet solution turned orange, and an orange precipitate was obtained.…”

Section: Synthesesmentioning

confidence: 98%

“…[2][3][4] The redox noninnocence of such molecules imparts many interesting properties to them. [5][6][7][8][9][10][11][12] Thus, metal complexes of quinonoid ligands have been extensively investigated due to their valence ambiguity and captivating electronic structures, [13][14][15][16][17][18] their engrossing magnetic properties, [19][20][21][22] their use as bridges for molecular and supramolecular systems, [19,[23][24][25][26][27][28][29][30][31][32][33][34][35][36] and in homogeneous catalysis.…”

Section: Introductionmentioning

confidence: 99%

Ruthenium Hydride Complexes with Zwitterionic Quinonoid Ligands – Isomer Separation, Structural Properties, Electrochemistry, and Catalysis

2011

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Reactions of [Ru(PPh3)3(CO)(H)Cl] with the zwitterionic p‐benzoquinonemonoimine‐type ligands 4‐(n‐butylamino)‐6‐(n‐butylimino)‐3‐oxocyclohexa‐1,4‐dien‐1‐olate (Q1), 4‐(isopropylamino)‐6‐(isopropylimino)‐3‐oxocyclohexa‐1,4‐dien‐1‐olate (Q2), and 4‐(benzylamino)‐6‐(benzylimino)‐3‐oxocyclohexa‐1,4‐dien‐1‐olate (Q3) in the presence of a base led to the formation of mononuclear complexes [Ru(PPh3)2(CO)(H)(Q1–H)] (1a and 1b), [Ru(PPh3)2(CO)(H)(Q2–H)] (2a and 2b), and [Ru(PPh3)2(CO)(H)(Q3–H)] (3a and 3b), respectively. The positional isomers (a and b) that were formed in each case were separated by preparative TLC. The structural characterization of 2a and 3a·MeCN helped to identify the isomers, and established the distorted octahedral coordination geometry around the ruthenium center. The bond lengths in the complexes are consistent with localization of the double bonds in Q2–H and Q3–H in both their monodeprotonated and metal‐coordinated forms. The Ru–C–O(carbonyl) bond angle is almost linear. Cyclic voltammetry of the complexes showed one oxidation and one reduction process. These are predominantly centered on the quinonoid ligands, which shows their redox‐noninnocent character. Studies of transfer hydrogenation with 2a as a precatalyst showed that, in the presence of KOH, acetophenone could be converted to 1‐phenylethanol within 10 h in over 90 % yield.

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Metallo‐ROS in Alzheimer's Disease: Oxidation of Neurotransmitters by Cu^II‐β‐Amyloid and Neuropathology of the Disease

Cited by 14 publications

References 64 publications

Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis

Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis

Methionine does not reduce Cu(II)–β-amyloid!—Rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)–β-amyloid

Ruthenium Hydride Complexes with Zwitterionic Quinonoid Ligands – Isomer Separation, Structural Properties, Electrochemistry, and Catalysis

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Metallo‐ROS in Alzheimer's Disease: Oxidation of Neurotransmitters by CuII‐β‐Amyloid and Neuropathology of the Disease

Cited by 14 publications

References 64 publications

Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis

Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis

Methionine does not reduce Cu(II)–β-amyloid!—Rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)–β-amyloid

Ruthenium Hydride Complexes with Zwitterionic Quinonoid Ligands – Isomer Separation, Structural Properties, Electrochemistry, and Catalysis

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Metallo‐ROS in Alzheimer's Disease: Oxidation of Neurotransmitters by Cu^II‐β‐Amyloid and Neuropathology of the Disease