Redox-active Cu(II)–Aβ causes substantial changes in axonal integrity in cultured cortical neurons in an oxidative-stress dependent manner

Howells, Claire; Saar, Katrina; Eaton, Emma D.; Ray, Shannon; Palumaa, Peep; Shabala, Lana; Adlard, Paul A.; Bennett, Bill; West, Adrian K.; Guillemin, Gilles J.; Chung, Roger S.

doi:10.1016/j.expneurol.2012.06.002

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…We previously showed that oxidative damage precedes tau pathology in the P301S mice, and it also occurs in a hippocampal slice model of tau toxicity (20,39). The copper (II) beta-amyloid (Cu(II)-Ab) complex, a toxic form of Ab, increases free radical generation and produces hyperphosphorylated tau-containing axonal swellings (40). This indicates that oxidative stress can drive tau pathology, which is substantiated by the finding that the B-27 supplement, a cocktail of antioxidants and the antioxidant curcumin prevent the formation of these large axonal swellings (40).…”

Section: Discussionmentioning

confidence: 99%

“…The copper (II) beta-amyloid (Cu(II)-Ab) complex, a toxic form of Ab, increases free radical generation and produces hyperphosphorylated tau-containing axonal swellings (40). This indicates that oxidative stress can drive tau pathology, which is substantiated by the finding that the B-27 supplement, a cocktail of antioxidants and the antioxidant curcumin prevent the formation of these large axonal swellings (40). In P301S mice, both the MB low dose diet and MB high dose diet decreased the immunoreactivity of 8-OHdG in the cerebral cortex and the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

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Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity

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Jainuddin

Elipenahli

et al. 2014

Human Molecular Genetics

121

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Methylene blue (MB, methylthioninium chloride) is a phenothiazine that crosses the blood brain barrier and acts as a redox cycler. Among its beneficial properties are its abilities to act as an antioxidant, to reduce tau protein aggregation and to improve energy metabolism. These actions are of particular interest for the treatment of neurodegenerative diseases with tau protein aggregates known as tauopathies. The present study examined the effects of MB in the P301S mouse model of tauopathy. Both 4 mg/kg MB (low dose) and 40 mg/kg MB (high dose) were administered in the diet ad libitum from 1 to 10 months of age. We assessed behavior, tau pathology, oxidative damage, inflammation and numbers of mitochondria. MB improved the behavioral abnormalities and reduced tau pathology, inflammation and oxidative damage in the P301S mice. These beneficial effects were associated with increased expression of genes regulated by NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE), which play an important role in antioxidant defenses, preventing protein aggregation, and reducing inflammation. The activation of Nrf2/ARE genes is neuroprotective in other transgenic mouse models of neurodegenerative diseases and it appears to be an important mediator of the neuroprotective effects of MB in P301S mice. Moreover, we used Nrf2 knock out fibroblasts to show that the upregulation of Nrf2/ARE genes by MB is Nrf2 dependent and not due to secondary effects of the compound. These findings provide further evidence that MB has important neuroprotective effects that may be beneficial in the treatment of human neurodegenerative diseases with tau pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity

Stack

Jainuddin

Elipenahli

et al. 2014

Human Molecular Genetics

121

View full text Add to dashboard Cite

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“…However, studies on the impact of dietary copper on neurodegenerative diseases in humans are less convincing [42,43], suggesting that it is ] = 36 μM, T = 20.5°C, pO 2 = ambient, k 1 = first-order rate constant for iron oxidation. Data adapted from Howells et al [51].…”

Section: Copper and Iron In Chronic Diseasementioning

confidence: 99%

“…Eaton, Monnier, and colleagues [52,53] as outlined in Figure 1. Analogous to the binding of copper to AGEs in the vascular wall and extracellular matrix in diabetes and atherosclerosis, copper also binds strongly to β-amyloid proteins in neuronal plaques and in a redoxactive, catalytically active, ROS-generating form [51,54]. The catalytic role of copper explains the effect of copper chelators alone in treatment of diabetes, atherosclerosis, and neurodegenerative disease and also the enrichment of iron in atherosclerotic and neurodegenerative plaque.…”

Section: Hypothesismentioning

confidence: 99%

Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma

Frizzell

Baynes

2014

Clinical Chemistry and Laboratory Medicine

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Evidence in support of this hypothesis included the observation that many drugs used in the treatment of diabetes are chelators, that advanced glycation end product (AGE) inhibitors and AGE breakers lack carbonyl-trapping or AGE-breaker activity but are potent chelators, and that simple copper chelators inhibit vascular pathology in diabetes and aging. In the present article, we extend this hypothesis, proposing the interplay between copper and iron in the development of pathology in diabetes and other chronic age-related diseases, including atherosclerosis and neurodegenerative diseases. We also discuss the need and provide a framework for the development of a clinical laboratory test to assess plasma autoxidative catalytic activity and transition metal homeostasis in vivo.

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Copper in Brain and Neurodegeneration

Liddell

Bush

White

2004

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Cu is an essential element for the brain. It is involved in neurotransmission and is required for several cuproenzymes of the brain. Cu deficiency and Cu excess are associated with Menkes disease and Wilson's disease, respectively, and the importance of Cu in the brain is amply illustrated by the severe neurological symptoms elicited by these diseases. Disruption of Cu homeostasis is also evident in complex neurodegenerative diseases and is implicated in their pathogenesis. Cu influences the regulation and aggregation of key Alzheimer's disease ( AD ) neuropathological proteins such as amyloid precursor protein, amyloid‐β, and tau. Parkinson's disease ( PD ) is associated with a decreased Cu content of the substantia nigra, the brain region that is affected in the disease. Cu also promotes the aggregation of α‐synuclein, the predominant protein present in the characteristic Lewy bodies of PD brain, and huntingtin, found in inclusions in Huntington's disease. Mutant SOD1 is thought to have a toxic gain of function in amyotrophic lateral sclerosis, possibly caused by Zn‐deficient CuSOD1 . Niemann‐Pick type C disease ( NPC ) is caused by mutations in the NPC gene, giving rise to impaired NPC protein. Evidence suggests that NPC may be involved in Cu metabolism. The involvement of Cu in these diseases is highlighted by the efficacy of therapeutics targeting the redistribution of Cu. Cu ionophores such as clioquinol and PBT2 bind endogenous Cu, transport it into cells and induce multiple cellular pathways. In AD , these ionophores likely sequester Cu bound to amyloid‐β plaques. Preformed bis(thiosemicarbazone)‐Cu complexes deliver exogenous Cu into the brain and induce similar pathways to the ionophores. These Cu complexes have shown efficacy in animal models of several neurodegenerative diseases, and the cellular pathways induced are being elucidated. These therapeutic outcomes, together with improved resolution of techniques for identifying Cu distribution in brain cells, are providing valuable new insights into the role of Cu in neuronal and glial cell homeostasis.

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Redox-active Cu(II)–Aβ causes substantial changes in axonal integrity in cultured cortical neurons in an oxidative-stress dependent manner

Cited by 6 publications

References 27 publications

Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity

Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity

Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma

Copper in Brain and Neurodegeneration

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