Molecular mechanisms underlying copper function and toxicity in neurons and their possible therapeutic exploitation for Alzheimer’s disease (original) (raw)
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Journal of Alzheimer's disease : JAD, 2015
Copper is an essential micronutrient for physiological cell functioning and central nervous system (CNS) development. Indeed, it is a cofactor of many proteins and enzymes in a number of molecular pathways, including energy generation, oxygen transportation, hematopoiesis, cellular growth and metabolism, and signal transduction. This is because it serves as a catalyst of reduction-oxidation (redox) reactions in these processes. When copper is kept under control, bound to special proteins, it yields key properties. However, when it spirals out of control, it is exchanged among small compounds (it is loosely bound to them), and its redox activity makes it dangerous for cell viability, promoting oxidative stress. Copper homeostasis in the CNS is securely synchronized, and perturbations in brain copper levels are known to underlie the pathoetiology of wide spectrum of common neurodegenerative disorders, including Alzheimer's disease. The main objective of this review is to provide s...
Copper-induced alterations in rat brain depends on route of overload and basal copper levels
Nutrition, 2014
Objectives: Copper (Cu) is widely used in industry for the manufacture of a vast range of goods including Cu-intrauterine devices (IUDs), electronic products, agrochemicals, and many others. It is also one of the trace elements essential to human health in the right measure and is used as a parenteral supplement in patients unable to ingest food. Elevated Cu levels have been found in the plasma of women using Cu-IUDs and in farmers working with Cu-based pesticides. However, possible alterations due to Cu overload in the brain have been poorly studied. Therefore, the aim of this study was to investigate the effects of Cu administration on rat brain in Cu-sufficient and Cudeficient animals fed on semi-synthetic diets with different doses of Cu (7 or 35 ppm). Methods: We aimed to investigate the effects of Cu administration using two routes of administration: oral and intraperitoneal (IP). Male Wistar rats were feeding (one month) a complete (7 ppm) or a deficient (traces) Cu diets subdivided into three categories oral-, intraperitoneal-(or both) supplemented with copper carbonate (7 to 35 ppm). Cu content in plasma, brain zones (cortex and hippocampus), antioxidant enzyme activities, and protease systems involved in programmed cell death were determined. Results: The results show that Cu levels and the concentration of Cu in plasma and brain were dosedependent and administration route-dependent and demonstrated a prooxidative effect in plasma and brain homogenates. Oxidative stress biomarkers and antioxidative enzyme activity both increased under Cu overload, these effects being more noticeable when Cu was administered IP. Concomitantly, brain lipids from cortex and hippocampus were strongly modified, reflecting Cuinduced prooxidative damage. A significant increase in the activities of calpain (milli-and micro-) and caspase-3 activity also was observed as a function of dose and administration route. Conclusion: The findings of this study could be important in evaluating the role of Cu in brain metabolism and neuronal survival.
Role of copper in human neurological disorders
The American Journal of Clinical Nutrition, 2008
Copper is a trace element present in all tissues and is required for cellular respiration, peptide amidation, neurotransmitter biosynthesis, pigment formation, and connective tissue strength. Copper is a cofactor for numerous enzymes and plays an important role in central nervous system development; low concentrations of copper may result in incomplete development, whereas excess copper maybe injurious. Copper may be involved in free radical production, via the Haber-Weiss reaction, that results in mitochondrial damage, DNA breakage, and neuronal injury. Evidence of abnormal copper transport and aberrant copper-protein interactions in numerous human neurological disorders supports the critical importance of this trace metal for proper neurodevelopment and neurological function. The biochemical phenotypes of human disorders that involve copper homeostasis suggest possible biomarkers of copper status that may be applicable to general populations.
Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer's disease
Prion
A dysfunction in copper homeostasis seems to occur in Alzheimer's disease (AD). We recently demonstrated that an excess of non-ceruloplasmin-copper (i.e., 'free' copper) correlates with the main functional and anatomical deficits as well as the cerebrospinal markers of the disease, thus suggesting that copper contributes to AD neurodegeneration. Aim of this study was to investigate the profile of serum ceruloplasmin isoforms immunoreactive protein in relation to copper dysfunction in AD. Twenty-five AD patients and 25 controls were included in the study. All subjects underwent individual measurements of serum ceruloplasmin and copper concentrations, and the amount of 'free' copper was computed for each copper and ceruloplasmin pair. Serum samples were also pooled and analyzed by two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and western blot analysis. The mean concentration of 'free' copper resulted higher in AD patients than in controls. C...
Journal of Alzheimer's Disease, 2021
The cause of Alzheimer’s disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energ...
Copper and Ceruloplasmin Abnormalities in Alzheimer’s Disease
American Journal of Alzheimer's Disease & Other Dementiasr, 2010
The idea that copper may play a role in the pathogenesis of Alzheimer’s disease is gaining momentum. Serum copper and ceruloplasmin were measured by both enzymatic (eCp) and immunologic (iCp) methods in 28 patients with Alzheimer’s disease and 29 age-matched controls. ‘‘Free copper’’ was determined by subtracting copper accounted for in the eCp assay from total serum copper. Percentage free copper, that is the proportion of serum copper not bound to ceruloplasmin, was significantly elevated in patients with Alzheimer’s compared to controls. There was significantly more ‘‘defective’’ ceruloplasmin, which is apoceruloplamin lacking its copper, in Alzheimer’s disease than in normal controls. This abnormality may precede the clinical onset of the disease and help predict risk of disease onset. Increased exposure to environmental copper (eg, the spread of copper plumbing and the use of copper in supplements) and/or defective ceruloplasmin function may play a role in the current epidemic ...
Agents Complexing Copper as a Therapeutic Strategy for the Treatment of Alzheimers Disease
Current Alzheimer Research, 2009
The notion that a copper dysfunction is implicated in Alzheimer's disease (AD) is based on a number of observations from in vitro and clinical studies, as well as animal models. However, there is still significant controversy over whether it is an excess or a deficiency of copper to be involved in the pathogenesis of AD. Numerous studies support the hypothesis that an excess of copper contributes to AD, but experimental evidence in transgenic mouse models seems to suggest the contrary, and at least one clinical study shows that cognitive decline correlates positively with low copper levels. We have recently reported on a deregulation of the ceruloplasmin-copper relationship, specific to AD patients, consisting of an elevation of the copper pool not bound to ceruloplasmin, i.e. 'free' copper. This phenomenon could provide an explanation of the contrasting results obtained in clinical studies. Several clinical trials have been attempted in search of an anti-metal effect counteracting AD progression. Some of them have delivered encouraging results indicating that "metal protein attenuating compounds" can indeed alter positively the progression of the disease. This review summarizes these clinical studies and provides an overview of those in progress and in preparation.
Inorganics, 2022
Alzheimer’s disease is a progressive neurodegenerative disorder that eventually leads the affected patients to die. The appearance of senile plaques in the brains of Alzheimer’s patients is known as a main symptom of this disease. The plaques consist of different components, and according to numerous reports, their main components include beta-amyloid peptide and transition metals such as copper. In this disease, metal dyshomeostasis leads the number of copper ions to simultaneously increase in the plaques and decrease in neurons. Copper ions are essential for proper brain functioning, and one of the possible mechanisms of neuronal death in Alzheimer’s disease is the copper depletion of neurons. However, the reason for the copper depletion is as yet unknown. Based on the available evidence, we suggest two possible reasons: the first is copper released from neurons (along with beta-amyloid peptides), which is deposited outside the neurons, and the second is the uptake of copper ions ...
Copper imbalance and oxidative stress in neurodegeneration
The Italian journal of biochemistry
Much experimental evidence demonstrates that the increased production of free radicals and oxidative damage due to alterations in copper homeostasis (because of either deficit or excess or aberrant coordination of the metal) are involved in the neurodegenerative processes occurring in many disorders of the central nervous system. This review outlines the systems that are involved in copper homeostasis and in the control of copper redox reactivity. The mechanisms underlying neurodegeneration in the acknowledged genetic disturbances of copper homeostasis, namely Menkes' and Wilson's diseases, and the involvement of copper in the aetiology of the major neurodegenerative disease of the aging brain, Alzheimer's disease, will be described, with particular focus on oxidative stress.