Copper Abstracts 1


Role of copper and cholesterol association in the neurodegenerative process.
            (Arnal et al., 2013) Download
Age is one of the main factors involved in the development of neurological illnesses, in particular, Alzheimer, and it is widely held that the rapid aging of the world population is accompanied by a rise in the prevalence and incidence of Alzheimer disease. However, evidence from recent decades indicates that Cu and Cho overload are emerging causative factors in neurodegeneration, a hypothesis that has been partially investigated in experimental models. The link between these two variables and the onset of Alzheimer disease has opened up interesting new possibilities requiring more in-depth analysis. The aim of the present study was therefore to investigate the effect of the association of Cu + Cho (CuCho) as a possible synergistic factor in the development of an Alzheimer-like pathology in Wistar rats. We measured total- and nonceruloplasmin-bound Cu and Cho (free and sterified) contents in plasma and brain zones (cortex and hippocampus), markers of oxidative stress damage, inflammation, and programmed cell death (caspase-3 and calpain isoforms). The ratio beta-amyloid (1-42)/(1-40) was determined in plasma and brain as neurodegenerative biomarker. An evaluation of visuospatial memory (Barnes maze test) was also performed. The results demonstrate the establishment of a prooxidative and proinflammatory environment after CuCho treatment, hallmarked by increased TBARS, protein carbonyls, and nitrite plus nitrate levels in plasma and brain zones (cortex and hippocampus) with a consequent increase in the activity of calpains and no significant changes in caspase-3. A simultaneous increase in the plasma A β 1-42/A β 1-40 ratio was found. Furthermore, a slight but noticeable change in visuospatial memory was observed in rats treated with CuCho. We conclude that our model could reflect an initial stage of neurodegeneration in which Cu and Cho interact with one another to exacerbate neurological damage.

Could chronic wounds not heal due to too low local copper levels
            (Borkow et al., 2008) Download
Copper is an essential trace element involved in numerous human physiological and metabolic processes. It plays a key role in many of the processes that together comprise wound healing, including induction of endothelial growth factor, angiogenesis and expression and stabilization of extracellular skin proteins. We hypothesize that in individuals with diabetic ulcers, decubitus, peripheral vascular, or other wounds which might have compromised circulation to the wound site, that part of the incapacity of the wounds to heal is due to low local copper levels. Contamination of wounds is also an important factor causing impaired wound healing. Importantly, copper has potent broad biocidal properties. In contrast, the risk of adverse skin reactions due to exposure to copper is extremely low. We thus hypothesize that introducing copper into wound dressings would not only reduce the risk of wound and dressing contamination, as silver does but, more importantly, would stimulate faster wound repair directly. This would be done by the release of copper from the wound dressings directly into the wound site inducing angiogenesis and skin regeneration.

Speciation of copper in a range of food types by X-ray absorption spectroscopy.
            (Ceko et al., 2014) Download
Copper (Cu) is an essential element and the effects of diets deficient in it are well established. However, the effects of long-term high copper intake are less clear. The chemical form of copper from food sources and its resultant bioavailability is a potentially important factor in its biological activity. X-ray Absorption Near-Edge Structure (XANES) was used to determine the chemical forms of Cu in a range of foods that would make significant contributions to total copper absorption in a standard diet, as well as a chlorinated tap water sample. Analysis of the Cu K-edge XANES spectra suggested that Cu existed in both Cu(I) and Cu(II) forms, with the following five model compounds: Cu(I) acetate; Cu(II) acetate; Cu(I)-glutathione; Cu(I)-cysteine; and, Cu(II)-histidine being fitted to the sample spectra. This research suggested that the absorption of dietary copper could vary markedly dependent on the types of food consumed and the different bioavailability of the Cu species they contain.

            (Collins and Klevay, 2011) Download
Copper is the 26th element in abundance in the crust of the earth and is the 29th element in the periodic table with 2 stable and 9 radioactive isotopes. Copper deficiency is the leading deficiency worldwide among nutritional diseases of agricultural animals. The essentiality of copper for animals and humans has been known for nearly a century. Needed in only trace amounts, the human body contains slightly >100 mg, although measurements are scarce. Only kidney and liver exceed the concentration of copper in brain (∼5 μg/g), with heart being close behind. These high concentrations are probably related to metabolic activity, because copper is a cofactor for cytochrome c oxidase, the terminal enzyme in the electron transport chain. Because of their size, skeleton and muscle contain more than one-half of the copper in the body.


The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens.
            (Djoko et al., 2015) Download
Zinc (Zn) and copper (Cu) are essential for optimal innate immune function, and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Consequently, a model has emerged in which the host utilizes Cu and/or Zn intoxication to reduce the intracellular survival of pathogens. This review describes and assesses the potential role for Cu and Zn intoxication in innate immune function and their direct bactericidal function.

Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.
            (Gerber et al., 2017) Download
Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn(2+) induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC50 value of 15 μm Importantly, at this concentration, Zn(2+) also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn(2+)-dependent APP-C99 dimerization and inhibition of Aβ production, whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn(2+) binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD.


Methods of assessment of copper status in humans: a systematic review.
            (Harvey et al., 2009) Download
BACKGROUND:  The assessment of dietary adequacy of copper is constrained by the absence of recognized copper status biomarkers. OBJECTIVES:  The objectives were to systematically review the usefulness of copper status biomarkers and identify those that reflected changes in status over > or =4 wk. DESIGN:  The methods included a structured search on Ovid MEDLINE, EMBASE (Ovid), and Cochrane databases to October 2007, followed by the use of formal inclusion/exclusion criteria, data extraction, validity assessment, and meta-analysis. RESULTS:  A total of 16 studies (288 participants) were included in the review, with data on 16 possible copper biomarkers. All of the included studies were small and at high risk of bias. Data for serum copper suggested its value as a biomarker, reflecting changes in status in both depleted and replete individuals, although these changes were smaller in the latter. Total ceruloplasmin protein is related to copper status but reflects changes in highly depleted individuals only. Erythrocyte superoxide dismutase and urinary deoxypyridinoline are not useful biomarkers, but there were insufficient data to draw firm conclusions about plasma, erythrocyte, and platelet copper; leukocyte superoxide dismutase; erythrocyte, platelet, and plasma glutathione peroxidase; platelet and leukocyte cytochrome-c oxidase; total glutathione; diamine oxidase; and urinary pyridinoline. The paucity of data prevented detailed subgroup analysis. CONCLUSIONS:  Despite limited data, serum copper appears to be a useful biomarker of copper status at the population level. Further large studies with low risk of bias are needed to explore the effectiveness of other biomarkers of copper status and the relation between biomarker responsiveness, dose, and period of supplementation.

Zinc treatment of Wilson's disease.
            (Hoogenraad, 1998) Download
In this issue the readers of the Journal will find a report presented by Brewer et al. 1 on maintenance treatment of hereditary copper intoxication (Wilson's disease) with zinc. The authors present data supporting the idea that zinc is completely effective and safe, and they recommend as the standard dose 50 mg zinc 3 times daily. The authors also state that zinc has been approved by the Food and Drug Administation for the treatment of Wilson's disease but that the label indication so far granted is for maintenance therapy only. I will try to set the article in its context and to provide some basic information on the subject.


Disturbed copper bioavailability in Alzheimer's disease.
            (Kaden et al., 2011) Download
Recent data from in vitro, animal, and human studies have shed new light on the positive roles of copper in many aspects of AD. Copper promotes the non-amyloidogenic processing of APP and thereby lowers the Aβ production in cell culture systems, and it increases lifetime and decreases soluble amyloid production in APP transgenic mice. In a clinical trial with Alzheimer patients, the decline of Aβ levels in CSF, which is a diagnostic marker, is diminished in the verum group (8 mg copper/day), indicating a beneficial effect of the copper treatment. These observations are in line with the benefit of treatment with compounds aimed at normalizing metal levels in the brain, such as PBT2. The data reviewed here demonstrate that there is an apparent disturbance in metal homeostasis in AD. More research is urgently needed to understand how this disturbance can be addressed therapeutically.

Copper modulation as a therapy for Alzheimer's disease
            (Manso et al., 2011) Download
The role of metals in the pathophysiology of Alzheimer's disease (AD) has gained considerable support in recent years, with both in vitro and in vivo data demonstrating that a mis-metabolism of metal ions, such as copper and zinc, may affect various cellular cascades that ultimately leads to the development and/or potentiation of AD. In this paper, we will provide an overview of the preclinical and clinical literature that specifically relates to attempts to affect the AD cascade by the modulation of brain copper levels. We will also detail our own novel animal data, where we treated APP/PS1 (7-8 months old) mice with either high copper (20 ppm in the drinking water), high cholesterol (2% supplement in the food) or a combination of both and then assessed β-amyloid (Aβ) burden (soluble and insoluble Aβ), APP levels and behavioural performance in the Morris water maze. These data support an interaction between copper/cholesterol and both Aβ and APP and further highlight the potential role of metal ion dyshomeostasis in AD.

How copper traverses cellular membranes through the mammalian copper transporter 1, Ctr1.
            (Ohrvik and Thiele, 2014) Download
The copper transporter 1, Ctr1, is part of a major pathway for cellular copper (Cu) uptake in the intestinal epithelium, in hepatic and cardiac tissue, and likely in many other mammalian cells and tissues. Here, we summarize what is currently known about how extracellular Cu travels across the plasma membrane to enter the cytoplasm for intracellular distribution and for use by proteins and enzymes, the physiological roles of Ctr1, and its regulation. As a critical Cu importer, Ctr1 occupies a strategic position to exert a strong modifying influence on diseases and pathophysiological states caused by imbalances in Cu homeostasis. A more thorough understanding of the mechanisms that regulate Ctr1 abundance, trafficking, and function will provide new insights and opportunities for disease therapies.

Trace copper levels in the drinking water, but not zinc or aluminum influence CNS Alzheimer-like pathology.
            (Sparks et al., 2006) Download
Mounting evidence suggests copper may influence the progression of Alzheimer's disease by reducing clearance of the amyloid beta protein (Abeta) from the brain. Previous experiments show that addition of only 0.12 PPM copper (one-tenth the Environmental Protection Agency Human consumption limits) to distilled water was sufficient to precipitate the accumulation of Abeta in the brains of cholesterol-fed rabbits (1). Here we report that addition of copper to the drinking water of spontaneously hypercholesterolemic Watanabe rabbits, cholesterol-fed beagles and rabbits, PS1/APP transgenic mice produced significantly enhanced brain levels of Abeta. In contrast to the effects of copper, we found that aluminum- or zinc-ion-supplemented distilled water did not have a significant effect on brain Ab accumulation in cholesterol-fed rabbits. We also report that administration of distilled water produced a reduction in the expected accumulation of Ab in three separate animal models. Collectively, these data suggest that water quality may have a significant influence on disease progression and Ab neuropathology in AD.

Excess of serum copper not related to ceruloplasmin in Alzheimer disease.
            (Squitti et al., 2005) Download
OBJECTIVE:  To assess the role of serum copper in relation to ceruloplasmin and other peripheral markers of inflammation in Alzheimer disease (AD). METHODS:  The authors studied serum levels of copper, ceruloplasmin, and transferrin, as well as total peroxides, antioxidants, and other peripheral markers of inflammation in 47 patients with AD, 24 patients with vascular dementia (VaD), and 44 healthy controls. Biochemical variables were related to the patients' and controls' clinical status. RESULTS:  The authors found that copper (p < 0.001), peroxides (p = 0.026), and ceruloplasmin (p = 0.052) were increased and TRAP was decreased (p = 0.006) in patients with AD, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in the serum of AD patients, but not of VaD or normal controls, of a large pool of non-ceruloplasmin-bound copper. CONCLUSIONS:  Changes in the distribution of the serum copper components, consisting of an increase of a copper fraction not explained by ceruloplasmin, seem to be characteristic of Alzheimer disease and may be implicated in the pathogenesis of the disease.

Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau.
            (Squitti et al., 2006) Download
OBJECTIVE:  To assess whether serum copper in Alzheimer disease (AD) correlates with cognitive scores, beta-amyloid, and other CSF markers of neurodegeneration. METHODS:  The authors studied copper, ceruloplasmin, total peroxide, and antioxidants levels (TRAP) in serum; beta-amyloid in plasma; and copper, beta-amyloid, h-tau, and P-tau in the CSF of 28 patients with AD and 25 healthy controls, in relation to clinical status. RESULTS:  Serum copper (p < 0.0001), peroxides (p = 0.002), a copper fraction unexplained by ceruloplasmin (p < 0.0001), and CSF h-tau (p = 0.001) were increased in AD, whereas serum TRAP (p = 0.03) and CSF beta-amyloid were decreased (p < 0.0001). Plasma beta-amyloid increased with age in healthy controls (r = 0.6; p = 0.05). CSF markers of AD correlated with serum copper variables. CSF copper was partially dependent on the serum copper fraction unexplained by ceruloplasmin (t = 2.2, p = 0.04). CSF beta-amyloid seemed to be related to serum copper (r = -0.46; p = 0.002). Mini-Mental Status Examination scores correlated positively with beta-amyloid (r = 0.46, p = 0.002) and inversely with copper unexplained by ceruloplasmin (r = -0.45, p = 0.003). CONCLUSIONS:  The authors' results confirm the existence of changes in copper component distribution, particularly the copper fraction unexplained by ceruloplasmin and support the hypothesis of a beta-amyloid and copper connection in Alzheimer disease.

Longitudinal prognostic value of serum "free" copper in patients with Alzheimer disease.
            (Squitti et al., 2009) Download
BACKGROUND:  Serum copper not bound to ceruloplasmin ("free") appears slightly elevated in patients with Alzheimer disease (AD). We explored whether a deregulation of the free copper pool can predict AD clinical worsening. METHODS:  We assessed levels of copper, iron, zinc, transferrin, ceruloplasmin, peroxides, total antioxidant capacity, free copper, and apolipoprotein E genotype in 81 patients with mild or moderate AD, mean age 74.4, SD = 7.4 years, clinically followed up after 1 year. The association among biologic variables under study and Mini-Mental State Examination (MMSE) (primary outcome), activities of daily living (ADL), and instrumental activities of daily living (IADL) (secondary outcomes) performed at study entry and after 1 year were analyzed by multiple regression. RESULTS:  Free copper predicted the annual change in MMSE, adjusted for the baseline MMSE by means of a linear regression model: it raised the explained variance from 2.4% (with only sex, age, and education) to 8.5% (p = 0.026). When the annual change in MMSE was divided into < 3 or > or = 3 points, free copper was the only predictor of a more severe decline (predicted probability of MMSE worsening 23%: odds ratio = 1.23; 95% confidence interval = 1.03-1.47; p = 0.022). Hyperlipidemic patients with higher levels of free copper seemed more prone to worse cognitive impairment. Free copper at baseline correlated with the ADL and IADL clinical scales scores at 1 year. CONCLUSIONS:  These results show an association between copper deregulation and unfavorable evolution of cognitive function in Alzheimer disease. Further research is needed to establish whether copper is an independent risk factor for cognitive decline.

Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease.
            (Squitti et al., 2014) Download
OBJECTIVE:  Meta-analyses show that nonbound ceruloplasmin (non-Cp) copper (also known as free or labile copper) in serum is higher in patients with Alzheimer disease (AD). It differentiates subjects with mild cognitive impairment (MCI) from healthy controls. However, a longitudinal study on an MCI cohort has not yet been performed to assess the accuracy of non-Cp copper for the prediction of conversion from MCI to AD during a long-term follow-up. METHODS:  The study included 42 MCI converters and 99 stable MCI subjects. We assessed levels of copper, ceruloplasmin, non-Cp copper, iron, transferrin, ferritin, and APOE genotype. A multiple Cox regression analysis-with age, sex, baseline Mini-Mental State Examination, APOE4, iron, non-Cp copper, transferrin, ferritin, hypercholesterolemia, and hypertension as covariates-was applied to predict the conversion from MCI to AD. RESULTS:  Among the evaluated parameters, the only significant predictor of conversion to AD was non-Cp copper (hazard ratio = 1.23, 95% confidence interval = 1.03-1.47, p = 0.022); for each additional micromole per liter unit (μmol/l) of non-Cp copper, the hazard increased by ~20%. Subjects with non-Cp copper levels >1.6 μmol/l had a hazard conversion rate (50% of conversion in 4 years) that was ~3× higher than those with values ≤1.6 μmol/l (<20% in 4 years). The rate of conversion was similar between APOE4 carriers and noncarriers (p = 0.321), indicating that the non-Cp copper association was independent of APOE4. INTERPRETATION:  Non-Cp copper appears to predict conversion from MCI to AD. These results encourage healthy life style choices and dietary intervention to modify this risk.

Diabetes and Alzheimer's Disease: Can Elevated Free Copper Predict the Risk of the Disease
            (Squitti et al., 2017) Download
BACKGROUND:  Defective copper regulation, primarily referred to as chelatable redox active Cu(II), has been involved in the etiology of diabetes, and Alzheimer's disease (AD). OBJECTIVES:  However, no study has determined levels of labile copper non-bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in the blood of subjects with diabetes compared with that of AD patients. METHODS:  To this aim, values of non-Cp Cu were measured in 25 Type 1 (T1D) and 31 Type 2 (T2D) subjects and in28 healthy controls, along with measurements of C-reactive protein, glycated hemoglobin A1c, cholesterol, and triglycerides. Non-Cp Cu levels were compared with those of an AD group previously studied. RESULTS:  T2D subjects had significantly higher non-Cp Cu levels than Controls and T1D subjects (both p < 0.001 after adjusting for age, sex, and body mass index). A multinomial logistic model revealed that a one unit standard deviation increase of non-Cp Cu increased the relative risk of having T2D by 9.64 with respect to Controls (95% CI: 2.86-32.47). The comparison of non-Cp Cu levels in T2D with those of an AD population previously studied shows rising blood non-Cp Cu copper levels from Controls to T2D and AD. CONCLUSION:  These results suggest the involvement of catalytically-active Cu(II) and glucose dysregulation in oxidative stress reactions leading to tissue damage in both diseases.




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Borkow, G, J Gabbay, and RC Zatcoff (2008), ‘Could chronic wounds not heal due to too low local copper levels’, Med Hypotheses, 70 (3), 610-13. PubMed: 17689198
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Djoko, KY, et al. (2015), ‘The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens.’, J Biol Chem, 290 (31), 18954-61. PubMed: 26055706
Gerber, H, et al. (2017), ‘Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production.’, J Biol Chem, 292 (9), 3751-67. PubMed: 28096459
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Hoogenraad, TU (1998), ‘Zinc treatment of Wilson’s disease.’, J Lab Clin Med, 132 (4), 240-41. PubMed: 9794692
Kaden, D, et al. (2011), ‘Disturbed copper bioavailability in Alzheimer’s disease.’, Int J Alzheimers Dis, 2011 345614. PubMed: 22145082
Manso, Y, et al. (2011), ‘Copper modulation as a therapy for Alzheimer’s disease’, Int J Alzheimers Dis, 2011 370345. PubMed: 21876828
Ohrvik, H and DJ Thiele (2014), ‘How copper traverses cellular membranes through the mammalian copper transporter 1, Ctr1.’, Ann N Y Acad Sci, 1314 32-41. PubMed: 24697869
Sparks, DL, et al. (2006), ‘Trace copper levels in the drinking water, but not zinc or aluminum influence CNS Alzheimer-like pathology.’, J Nutr Health Aging, 10 (4), 247-54. PubMed: 16886094
Squitti, R, et al. (2005), ‘Excess of serum copper not related to ceruloplasmin in Alzheimer disease.’, Neurology, 64 (6), 1040-46. PubMed: 15781823
Squitti, R, et al. (2006), ‘Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau.’, Neurology, 67 (1), 76-82. PubMed: 16832081
Squitti, R, et al. (2009), ‘Longitudinal prognostic value of serum “free” copper in patients with Alzheimer disease.’, Neurology, 72 (1), 50-55. PubMed: 19122030
Squitti, R, et al. (2014), ‘Value of serum nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease.’, Ann Neurol, 75 (4), 574-80. PubMed: 24623259
Squitti, R, et al. (2017), ‘Diabetes and Alzheimer’s Disease: Can Elevated Free Copper Predict the Risk of the Disease’, J Alzheimers Dis, 56 (3), 1055-64. PubMed: 27983558