
==== Front
Curr Neuropharmacol
Curr Neuropharmacol
CN
Current Neuropharmacology
1570-159X
1875-6190
Bentham Science Publishers

38037913
CN-22-1650
10.2174/1570159X22666231103085859
Medicine, Neurology, Pharmacology, Neuroscience
Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds
Zhong Guangcheng 1#
Wang Xinyue 2#
Li Jiaqi 1
Xie Zhouyuan 1
Wu Qiqing 1
Chen Jiaxin 1
Wang Yiyun 1
Chen Ziying 1
Cao Xinyue 1
Li Tianyao 1
Liu Jinman 3*
Wang Qi 1*
1 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China;
2 The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;
3 Affiliated Jiangmen TCM Hospital of Ji'nan University, Jiangmen, China
* Address correspondence to this author at the Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China; Tel: +8613002003167; E-mail: wangqi@gzucm.edu.cn
# These authors contributed equally to this work.
15 11 2023
2024
22 10 16501671
07 2 2023
23 5 2023
25 6 2023
© 2024 The Author(s). Published by Bentham Science Publishers
2024
The Author(s)
https://creativecommons.org/licenses/by/4.0/ © 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode.
Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.

Keywords

Neurodegenerative diseases
cognitive impairments
copper chelators
metal-protein attenuating compounds
natural compounds
polyphenol
==== Body
pmc1 INTRODUCTION

Neurodegenerative diseases are a heterogeneous group of diseases with severe dysfunction characterized by selective and progressive loss of specific neuronal functions [1]. Numerous studies have demonstrated that, despite the clinical symptoms of most neurological diseases being different, they share specific molecular and pathological features, such as oxidative stress [2], autophagy impairment [3], protein misfolding, and abnormal aggregation [4, 5]. Among the critical factors in various age-related neurodegenerative diseases is the breakdown of metal homeostasis in brain tissue [2]. In particular, it is closely related to the metabolic dysregulation of copper (Cu) in the brain [6, 7].

Copper occurs naturally in soil and groundwater and is an electrically conductive and ductile metal used throughout the world for centuries. Foods such as animal liver, nuts, legumes, fish, shrimp, and shellfish contain high levels of copper, whereas dairy products contain low levels [8]. For example, sheep liver contains 157 mg/kg copper, lobster contains 36.6 mg/kg copper [9], nuts such as hazelnuts and cashew nuts contain 14.8-22.5 mg/kg copper [10], while dairy products such as milk, yogurt, and cheese contain about 50-120 μg/L of copper [11]. Under physiological conditions, the body of a healthy adult contains approximately 110 mg of copper, of which approximately two-thirds are distributed in bones and muscles. Moreover, copper is primarily distributed in the liver (10 mg), brain (8.8 mg), and blood (6 mg) [12]. As one of the transition metal elements necessary for the human body, copper acts as an electron acceptor or donor by converting between its two oxidation states, Cu+ (organic copper) and Cu2+ (inorganic copper), thereby participating in various reactions and playing a significant role [8, 13]. Copper is a fundamental structural component and essential cofactor of many enzymes, including copper/zinc-superoxide dismutase (Cu/Zn SOD or SOD1) (antioxidant defense), ceruloplasmin (Cp) (iron metabolism), cytochrome c oxidase (CCO) (energy metabolism), tyrosinase (pigmentation), peptidylglycine-α-amidating enzyme (neuropeptide synthesis) and dopamine-β-monooxygenase (neurotransmission), all of which are dependent on copper for their catalytic activity [14-16]. Furthermore, copper is involved in many biological processes, including angiogenesis, connective tissue formation, catecholamine biosynthesis, and myelination [17, 18]. The body maintains copper levels within the normal range through precise homeostatic control mechanisms, including copper's absorption, transport, and excretion. Intracellular copper metabolism must be tightly controlled since elevated or decreased copper levels may cause neurotoxicity through different mechanisms. For example, when copper is overloaded, its redox activity enables it to catalyze the production of reactive oxygen species (ROS), including hydroxyl radicals (OH-), superoxide anions (O2-), and hydrogen peroxide (H2O2) through Fenton and Haber-Weiss reactions, which leads to oxidative damage to proteins, lipids, and deoxyribonucleic acid (DNA), resulting in neuronal dysfunction and cell death [8, 14, 17]. There is evidence that excessive copper contributes to the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Wilson's disease (WD) [17]. Copper deficiency reduces the body's ability to scavenge free radicals because copper acts as a cofactor in many antioxidant enzymes [19]. In addition, in the nervous system, copper plays a key role in a variety of neuronal functions by regulating synaptic activity, neurotrophic-induced signaling cascades, and excitotoxic cell death, and is also closely related to the occurrence and development of AD, PD, and Menkes disease (MD) [17]. The recently reported cuproptosis also revealed the importance of copper homeostasis, which is a novel form of cell death that occurs through the direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. The aggregation of these copper-bound lipoylated mitochondrial proteins and the subsequent loss of iron-sulfur (Fe-S) cluster proteins induce proteotoxic stress and, ultimately, cell death [20, 21]. Given that several neurodegenerative diseases are strongly associated with abnormal copper homeostasis, correcting the disturbed copper homeostasis in the body and brain by copper chelation or supplementation may be a promising strategy for treating neurodegenerative diseases.

Traditional Chinese Medicine (TCM) has long been used in the treatment and prevention of neurodegenerative diseases. It has unique advantages and potential for neurodegenerative diseases with complex pathogenesis due to its multi-component, multi-target, and multi-functional characteristics [22, 23]. In this paper, we reviewed the function and metabolism of copper (Fig. 1) and analyzed the potential relationship between copper metabolism and several neurodegenerative diseases (Table 1), including AD, PD, Huntington's disease (HD), ALS, WD, MD, prion diseases, and MS. In addition, this review also summarizes related drugs and therapies that regulate copper metabolism (Fig. 2) and natural compounds with the potential to improve neurodegenerative diseases by regulating copper metabolism (Tables 2, 3), providing a scientific and theoretical basis for drug development for the treatment of neurodegenerative diseases.

2 COPPER METABOLISM IN THE BODY

In the body, cellular copper transport requires various membrane copper transporters, including copper transporter 1 (CTR1, SLC31A1), divalent metal transporter 1 (DMT1), P-type copper-transporting ATPase α (ATP7A) and β (ATP7B), as well as various copper chaperones, including antioxidant protein 1 (ATOX1), copper chaperone for CCO (COX17), and copper chaperone for superoxide dismutase (CCS). They are responsible for transporting copper across cell membranes and delivering it to specific intracellular targets, ensuring copper homeostasis within the body by precisely regulating intracellular copper levels [12] (Fig. 1). Ceruloplasmin is the main protein that carries copper in the blood, and it carries about 95% of the copper in plasma [24], while the remainder is bound to albumin, transcuprein, and amino acids, called “free copper,” also known as non-ceruloplasmin-bound copper (Non-Cp-Cu) [25]. Dietary copper is absorbed into the body by enterocytes in the gastrointestinal tract and transported to the liver through portal circulation as free copper. In hepatocytes, copper is incorporated into ceruloplasmin, which transports copper from the liver to extrahepatic tissues, and excess copper is secreted into the bile and eventually excreted in the feces [26-29].

3 COPPER METABOLISM IN THE BRAIN

Copper concentration in the human brain is estimated to be 3.1 to 5.1 μg/g wet weight, but the distribution is not uniform. The highest copper content (11.40 ± 2.50 μg/g wet tissue weight) was found in the substantia nigra (SN), and high levels were also detected in the hippocampus, cerebellum, olfactory bulb, hypothalamus, and cortex [17, 30]. The homeostasis of the internal environment of brain tissue and central nervous system (CNS) is maintained by the coordinated action of the brain barrier system composed of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCB). The BBB is composed of tightly connected capillary endothelial cells of the brain that block harmful substances from entering the brain through the blood [31, 32]. In contrast, the BCB is located in the choroid plexus, a highly vascularized and polarized tissue in the roof of the ventricle whose primary function is to produce and secrete CSF [33]. In conclusion, the BBB is the primary route for copper entry into the brain, while the BCB is the primary route for copper efflux from the brain. Copper crosses the BBB as free copper ions and is transported from the blood circulation to the brain parenchyma, where it is released into the CSF, while the BCB returns copper from the CSF to the blood [15].

The copper transporters CTR1, ATP7A, and ATP7B are present in brain capillary endothelial cells and choroidal epithelial cells. They jointly regulate copper homeostasis in the brain and mediate copper influx into brain parenchyma and CSF. As the primary gatekeeper for copper entering the brain through brain capillary endothelial cells and choroid plexus epithelial cells, CTR1 is primarily located in the apical membrane of choroid plexus epithelial cells [26]. In the brain, astrocytes take up copper through CTR1 and sequester excess copper in MT and GSH complexes to protect cells from reactive oxygen and nitrogen species (ROS/RNS) [34]. Furthermore, DMT1 is an additional pathway for copper uptake in the brain [35]. ATP7A is expressed in endothelial cells of the BBB and facilitates the transport of copper in the blood across the basolateral membrane and into the extravascular space of the brain [36]. It is also strongly expressed in choroid plexus epithelial cells and mediates copper transport across the BBB and BCB [18]. In addition, excess copper can flow into the CSF, where it is taken up by CTR1 and DMT1 in the choroidal epithelial microvilli [12]. CTR1 and DMT1 mediate copper entry into neuronal cells after it reaches the CSF, then metallochaperones deliver copper to target pathways and ultimately participate in the metallation of copper enzymes [37], and ATP7A transports excess copper back into the blood from the CSF [33].

4 COPPER HOMEOSTASIS IN NEURODEGENERATIVE DISEASES

4.1 Alzheimer’s Disease

AD is the most common neurodegenerative disease [38] and is clinically characterized by memory impairment, progressive cognitive decline, and impaired executive function [31], affecting approximately 47 million people worldwide [39]. As one of the most prominent risk factors for AD, the size of the blood-free copper pool was significantly increased in AD patients (17.2 ± 5.9 μmol/L, n = 47) as compared to age-matched healthy controls (12.6 ± 2.5 μmol/L, n = 44) [40]. In addition, a positive correlation was found between the size of the blood-free copper pool and the degree of cognitive impairment, the speed of cognitive decline, and the risk of converting from mild cognitive impairment (MCI) to AD [13]. Autopsy analysis indicates that the copper content in amyloid plaques of AD patients (25.0 ± 7.8 μg/g, n = 9) is 5.7 times greater than in normal brains (4.4 ± 1.5 μg/g, n = 5) [41, 42]. In contrast, reduced copper levels in the brain have been found both in the hippocampal (AD: 12.6 ± 1.2 μg/g dry weight, n = 10; control:16.8 ± 0.9 μg/g, n = 11) and amygdala regions (AD:13.0 ± 1.5 μg/g, n = 10; control: 19.8 ± 1.5 μg/g, n = 11), which resulted in severe histopathological changes without significant changes in CSF copper levels [43, 44]. In addition, ceruloplasmin levels were significantly higher in most brain regions in patients (caudate: 1.29 ± 0.17 μg/g, putamen: 1.17 ± 0.07 μg/g, SN:0.62 ± 0.02 μg/g, hippocampus: 0.39 ± 0.05 μg/g, entorhinal cortex: 0.35 ± 0.04 μg/g, temporal cortex: 0.40 ± 0.05 μg/g, frontal cortex: 1.07 ± 0.07 μg/g, parietal cortex: 0.32 ± 0.03 μg/g, n = 12) compared to controls (caudate: 0.47 ± 0.05 μg/g, putamen:0.61 ± 0.14 μg/g, SN: 0.37 ± 0.07 μg/g, hippocampus:0.21 ± 0.02 μg/g, entorhinal cortex: 0.19 ± 0.02 μg/g, temporal cortex: 0.23 ± 0.01 μg/g, frontal cortex: 0.45 ± 0.11 μg/g, parietal cortex: 0.19 ± 0.02 μg/g, n = 7) [45, 46].

Amyloid precursor protein (APP), β-site APP cleaving enzyme 1 (BACE1), amyloid β (Aβ), and tubulin-associated unit (Tau) are proteins that bind copper and contribute to copper homeostasis in the brain. Animal experiments have shown that APP binds to Cu2+ and reduces it to Cu+. This conversion allows copper ions to be gradually cleared in the brain, which may explain the higher levels of serum copper and lower levels of brain copper in AD patients [43]. Mice overexpressing the APP gene had lower copper levels in the brain, whereas knocking out the APP gene showed the opposite result [47]. Copper binds to BACE1 and regulates its activity, thereby affecting the metabolism of APP [48]. Cu2+ binds to Aβ peptides with high affinity and increases the ratio of α-helix and β-sheet structures, which may be responsible for Aβ aggregation. The formed Cu-Aβ complex reduced the expression of low-density lipoprotein receptor-related protein-1 (LRP1) by activating microglia and promoting the release of inflammatory factors such as tumor necrosis factor-α (TNF-α), thus enhancing neuroinflammation and Aβ clearance disorder. ROS generated by the Cu-Aβ complex also led to oxidative damage of Aβ peptides, and the removal of Cu2+ from Aβ suppressed oxidative damage and reduced cell death [43]. Furthermore, copper promoted tau hyperphosphorylation and aggregation [49], whereas copper chelators reduced tau phosphorylation in SH-SY5Y cells [50]. Copper plays an essential role in regulating LRP1-mediated Aβ clearance. It promoted the downregulation of LRP1 in the brain capillaries in a mouse model of AD, partly due to the interaction of copper with LRP1 and cellular prions resulting in LRP1 nitrotyrosination and proteosomal degradation [51]. LRP1 is also known to bind tau and directly interact with Aβ, APP, and Apolipoprotein E4 (ApoE4), thereby regulating the production and clearance of Aβ [52]. The Apolipoprotein E (ApoE) allele is the genetic risk locus with the strongest association with AD, approximately a quarter of patients with sporadic AD carry the ApoE4 allele, and they are more susceptible to copper toxicity. ApoE2 and ApoE3 have copper-binding cysteine and significantly higher antioxidant activity than ApoE4, which has a lower capacity to bind copper due to the lack of copper-binding cysteine and is detrimental to Aβ clearance from the brain. Experimental studies confirmed that copper-induced Aβ aggregation was most pronounced when the ApoE4 allele was present and reduced the efflux of Aβ from the brain [26, 53]. Interestingly, genetic variants in the ATP7B gene are associated with a higher risk of AD since patients carrying mutants in the ATP7B gene have higher levels of free copper [54], and the ATP7B gene is also involved in sporadic AD [55].

4.2 Parkinson’s Disease

PD is the second most common neurodegenerative disease after AD and the neurological disease with the fastest-growing morbidity and mortality worldwide [56, 57]. It is characterized by resting tremor, muscle rigidity, bradykinesia, postural gait disturbance, and some non-motor symptoms [58]. Current evidence suggests that PD is associated with copper and iron homeostasis abnormalities. Reduced copper and increased iron content were found in the caudate nucleus (copper concentrations in PD: 0.36 ± 0.04 μg/g, n = 14; control: 0.63 ± 0.12 μg/g, n = 7) and SN (copper concentrations in PD: 0.60 ± 0.07 μg/g, n = 14; control: 0.86 ± 0.09 μg/g, n = 7) of PD patients [46, 59]. The main pathological changes in PD are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies formed by abnormal aggregation of soluble α-synuclein (α-syn) [60]. Copper binds α-syn with high affinity, promoting its aggregation and increasing oxidative stress [61]. Furthermore, copper and iron possess similar physicochemical properties and regulate each other in metabolic processes. In PD, copper deficiency may lead to iron deposition in the brain by affecting the activity of DMT1 and ceruloplasmin, affecting redox homeostasis and damaging dopaminergic neurons [59]. At the same time, elevated iron content may also lead to decreased concentrations of copper and ceruloplasmin in the brain [62]. In an iron-deficient rat model, copper levels in the brain parenchyma, CSF, and choroid plexus were significantly elevated, and copper transport in the brain was nearly doubled. In contrast, copper transport was reduced by about half in the brains of iron-overloaded rats [31]. In conclusion, the balance of these trace elements is crucial for maintaining copper homeostasis in the body.

4.3 Huntington’s Disease

HD is a rare autosomal dominant neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric deterioration. HD is caused by abnormal expansion of the cytosine-adenine-guanine (CAG) repeat sequence in exon 1 of the huntingtin (HTT) gene, which encodes the production of polyglutamine (polyQ). The repeated expansion of the CAG sequence leads to misfolding and abnormal aggregation of polyQ, which are major drivers of the translational production of mutant huntingtin (mHTT) and its toxic properties [63]. Abnormally elevated copper concentrations have been reported in the brains of HD patients and HD mouse models compared to controls [64, 65]. Particularly, copper levels in the putamen of HD patients (657 ± 126 nmol/g dry weight human brain, n = 4) increased by 64% compared to control patients (399 ± 35 nmol/g, n = 9), while copper levels in the SN of HD patients (1061 ± 229 nmol/g, n = 10) increased by 68% compared to control patients (629 ± 56 nmol/g, n = 10) [65]. However, many studies have demonstrated an increase in copper levels in the brain of HD patients; some studies reported no change or even a decrease in copper levels [66, 67]. Copper binds to HTT variants with 17 to 68 glutamine residues, whereas neither iron nor zinc binds to this region. Copper promotes the stable aggregation of HTT, while copper chelators inhibit this process [68]. In vitro and in vivo experiments revealed that copper increased the aggregation and toxicity of polyQ. Furthermore, copper interacts with histidine residues in the 171 amino acid N-terminal fragment of HTT, which may affect HTT fibril formation and oligomerization [64]. Notably, copper is also closely associated with inhibiting lactate dehydrogenase (LDH) activity in HD, which is instrumental in regulating lactate levels and providing neurons with energy substrates. In HD transgenic mice, lactate levels are elevated, and LDH activity is decreased. However, intrastriatal delivery of the LDH inhibitor Oxamate to normal mice resulted in HD-like neurodegeneration, and copper inhibited the activity of LDH, thereby inducing neurodegeneration in HD [45, 69]. The evidence that copper affects HTT aggregation and conformation and regulates energy metabolism supports the involvement of abnormal copper metabolism in the pathogenesis of HD.

4.4 Amyotrophic Lateral Sclerosis

ALS (Lou Gehrig's disease) is a progressive paralytic disease and the third most common neurodegenerative disease after AD and PD. It is characterized by muscle atrophy and paralysis resulting from the loss of upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Patients die within 2 to 5 years of diagnosis due to respiratory failure [70, 71]. ALS patients have elevated levels of copper ions in the motor cortex (ALS: 25.1 μg/g, control: 19.8 μg/g, n = 3-8) and decreased levels of copper ions (ALS: 913.21 ± 165.55 μg/L, n = 28; control: 1020.17 ± 197.76 μg/L, n = 38) and ceruloplasmin (ALS:23.2 ± 6.3 μg/L, n = 27; control: 25.0 ± 4.2 μg/L, n = 26) in the serum [27, 72-74]. In contrast, there have also been reports of decreased or no change in serum and CSF copper levels in patients with ALS compared with controls [45]. About 20% of familial ALS (FALS) cases are caused by mutations in the SOD1 gene, and approximately 150 SOD1 mutations have been identified [75]. The SOD1 gene encodes Cu/Zn SOD, which catalyzes the dismutation of O2.− into H2O2 and molecular oxygen, protecting cells from free radical damage and thus acting as an antioxidant enzyme [76]. SOD1 is a metalloprotein that forms highly stable homodimers by binding copper and zinc ions [77]. Mutations in SOD1 affect metal binding and may be defective in binding copper and zinc [78]. Dissociation of copper and/or zinc ions significantly lowers the melting temperature of SOD1, which makes it fail to resist the misfolding of the protein and significantly disturbs its native structure. Protein misfolding caused by metal dissociation of SOD1 is closely related to the progression of ALS [79]. Copper ions were abnormally accumulated in the spinal cords of patients (SALS: 89.0 ± 57.6 μg/g, n = 7; control: 46.3 ± 28.8 μg/g, n = 12) with sporadic ALS (SALS) and FALS model mice induced by overexpression of the mutant SOD1 gene [80-83]. Interestingly, there were no significant changes in SOD1 levels in the CSF of ALS patients (including SALS and those carrying SOD1 mutations) [84]. Transgenic mice overexpressing human mutant SOD1 have been shown to develop ALS-like symptoms, but not in mice knockout or overexpressing wild-type SOD1 genes, indicating that mutant SOD1 causes motor neuron disease by gaining toxic function rather than by losing normal physiological function [85]. Overall, mutant SOD1 may contribute to the development and progression of ALS by disrupting intracellular copper homeostasis and causing toxicity.

4.5 Wilson’s Disease

WD is a rare autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. In addition to clinical symptoms such as chronic hepatitis, cirrhosis, and liver failure, patients may experience neurological or psychiatric symptoms such as tremors, dysarthria, ataxia, Parkinson's syndrome, dystonia, anxiety, and depression. Diagnostic features include corneal pigmentation rings (Kayser-Fleischer rings) due to copper deposition in the cornea, decreased serum ceruloplasmin levels (< 200 mg/L), and elevated urinary copper levels (urinary copper excretion > 100 μg/24 h) [86-89]. In addition, genetic testing and liver biopsy (liver copper content > 250 μg/g dry weight) are also of great diagnostic significance [90]. The liver is the primary organ responsible for maintaining copper homeostasis. In the liver, ATP7B transports copper to the copper-dependent ferroxidase ceruloplasmin and regulates the export of excess copper to bile, which is eventually excreted in the feces [91]. Although ATP7B knockout mice exhibited hepatic copper overload at 6 weeks of age, they did not develop symptoms of WD at this time [92]. In WD, a defect in ATP7B function results in the inability of copper to be incorporated into ceruloplasmin and the dysfunctional excretion of copper into the bile, which ultimately leads to copper accumulation in various organs such as the liver, brain, and cornea, as well as reduced serum levels of ceruloplasmin [9]. Autopsy studies have shown that WD patients (n = 12) have significantly increased copper levels in the cortex (WD: 34.3 ± 17.5 μg/g; control: 3.6 ± 0.9 μg/g) and basal ganglia(WD: 36.6 ± 8.2 μg/g; control: 5.7 ± 0.7 μg/g), an eight-fold increase in brain copper levels compared to controls (WD: 41.0 ± 18.6 μg/g; control: 5.4 ± 1.8 μg/g) (n = 5) [93-95], and liver copper levels that are approximately 25 times higher than normal (WD: 417 ± 83 μg/g, n = 3; normal: 17 ± 9 μg/g, n = 8) [96, 97]. Urinary copper is derived from free copper circulating in the blood. In untreated WD, free copper pools can often be as high as 50 mg/dL, and it is this greatly elevated free copper that contributes to copper toxicity [98]. Furthermore, an excessive copper load leads to tissue failure and death by damaging mitochondria. The mitochondria were found to contain significantly higher copper loads than the nucleus and endoplasmic reticulum (ER) in the liver of WD patients, as well as changes in mitochondrial structure, including increased electron density, separated inner and outer membranes, and giant mitochondria, which were abolished with copper chelators [94].

4.6 Menkes Disease

MD is an X-linked recessive, lethal multisystem copper metabolic disease caused by mutations in the ATP7A gene. Most patients are males, and the main clinical features include progressive neurodegeneration, connective tissue abnormalities, and hair abnormalities [99]. As well as regulating neuronal activation and axonal development, ATP7A is essential for copper uptake across the intestinal mucosa and copper transport across the BBB and BCB. ATP7A transports copper to the TGN and delivers it to a series of copper-dependent enzymes [100] while also removing excess copper from the cytosol to maintain intracellular copper levels [101]. In MD, ATP7A dysfunction affects copper transport across the intestinal mucosa and the BBB, resulting in severe systemic copper deficiency [102]. Many symptoms can be attributed to the reduced activity of a range of copper-dependent enzymes, including CCO, tyrosinase, and lysyl oxidase, as demonstrated in animal models and MD patients [99]. However, copper is unevenly distributed in MD patients, with copper accumulating in their intestines and kidneys while significantly lower levels are found in the serum, liver, and brain [103]. In addition, plasma ceruloplasmin levels are lower in MD patients (0.04 g/L; normal range, 0.2-0.6 g/L) [104, 105].

4.7 Prion Diseases

Prion diseases (transmissible spongiform encephalopathies, TSEs) are a group of fatal neurodegenerative diseases affecting humans and animals caused by the conformational transition of normal cellular prion protein (PrPC) to the pathogenic associated isoform PrPSc [106]. Prion diseases are characterized by neurological symptoms such as extrapyramidal motor signs, cerebellar ataxia, and myoclonus [107]. Creutzfeldt-Jakob disease (CJD) is the most prevalent human prion disease, accounting for more than 85% of all cases [108, 109]. PrPC is a glycosylphosphatidylinositol (GPI)-anchored plasma membrane protein widely distributed throughout the body and predominantly expressed in the brain (CNS) and exhibits SOD-like activity when bound to copper [110]. PrPC also exhibits copper transporter properties, and its N-terminus contains a highly conserved octapeptide repeat sequence (PHGGGWGQ) with 5-6 Cu2+ binding sites [111]. PrPC has a series of physiological functions, such as immunoregulation [112], neuroprotection, antioxidant [113], signal transduction, and synaptic transmission [114]. PrPSc is a misfolded conformer of PrPC that differs in its structure. PrPC is mainly α-helix in structure, while PrPSc is rich in β-sheet. PrPSc aggregates can recruit PrPC protein through a self-perpetuating reaction and convert it to its own conformation [112], and the aggregation and precipitation of protease-resistant PrPSc is neurotoxic [68]. It has been reported that the copper content in the brain tissue of patients (4.23 ± 0.33 μg/g wet weight, n = 9) with sporadic Creutzfeldt-Jakob disease (sCJD) was reduced by 50% compared with the controls (6.44 ± 0.18 μg/g, n = 3) [115], and there is also a 60% reduction in brain copper levels in scrapie-infected mice, indicating a severe copper deficiency in prion diseases [116]. Furthermore, prion protein (PrP) knockout mice and PrPSc-infected mice had significantly lower copper levels in the brain than wild-type mice [107]. The potential mechanisms for prion neurotoxicity mainly include the loss of PrPC function and the gain of toxic function for PrPSc [117].

It is interesting to note that there is conflicting evidence regarding the role of copper in prion diseases. On the one hand, PrP requires copper to remain “normal” and non-infectious, and copper deficiency can lead to prion diseases. Copper acts as an antioxidant in copper-containing PrP, thereby enhancing neuronal survival [118]. Copper also inhibits its interaction with PrPSc by inducing endocytosis of PrPC from the cell surface, thereby reducing the spread of prion diseases [119]. Furthermore, PrPC and copper jointly inhibit N-methyl-D-aspartate receptors (NMDARs), which protect neurons from excitotoxicity [117]. In earlier studies, the copper chelator cuprizone was found to induce clinical symptoms similar to scrapie in mice [120]. According to another study, copper ions delayed the onset of prion diseases in scrapie-infected mice and significantly reduced the accumulation of PrPSc in scrapie-infected neuroblastoma cells [121]. All of this evidence suggests that copper plays a protective role in prion diseases. On the other hand, the binding of copper to PrPC promotes its conformational transition to PrPSc, increasing protease resistance and protein infectivity [82]. Treatment with the copper chelator D-penicillamine (DPA) delayed disease onset in scrapie-infected mice while reducing copper levels in the blood and brain [119]. In addition, Cu2+ is involved in the aggregation of human PrP, mainly through binding His-111, Met-109, and Met-112 to produce neurotoxicity [122]. These pieces of evidence support the role of copper in promoting prion diseases. As a result, copper plays a seemingly paradoxical role in the development of prion diseases, and its mechanism of action is still unclear. Possible reasons are that copper may act differently due to various factors, such as the copper-to-prion ratio, pH, and oxidation state [118].

4.8 Multiple Sclerosis

MS is an autoimmune inflammatory disease of the CNS and is the leading cause of neurological disability in young adults [123]. Clinical manifestations include gait disturbance, sensory disturbances, visual impairment, and cognitive deficits [124]. Copper concentrations in serum (MS: 16.44 ± 0.71 μmol/L, n = 29; control: 12.90 ± 1.09 μmol/L, n = 29) and CSF (MS: 0.171 ± 0.02 μmol/L, n = 28; control: 0.088 ± 0.01 μmol/L, n = 28) are significantly elevated in MS patients compared to healthy controls. The possible reason is that the decrease in serum ceruloplasmin activity affects the absorption of copper, leading to increased free copper [24]. Upregulated copper transporters have been found in the CNS of MS patients, and dysregulated copper transport may cause demyelination through astrocytes. In active MS lesions, structural and functional impairment of the BBB can lead to serum copper entry into the CNS, subsequent uptake and release of copper by astrocytes, and induction of demyelination. In contrast, in inactive MS lesions, copper uptake and distribution are also regulated by astrocytes. Notably, restoring copper homeostasis in the white matter may be a potential therapeutic target [125].

5 TARGETED DRUGS AND THERAPIES TO REGULATE COPPER HOMEOSTASIS

5.1 Metal-protein Attenuating Compounds (MPACs)

MPACs are a class of multifunctional compounds that, unlike traditional chelators, have a moderate affinity for bound metal ions and exhibit mild chelation [128]. They compete mildly with metal ions for target proteins and restore metal homeostasis by regulating metal ion redistribution and disrupting aberrant metal-protein interactions. Therefore, the mechanism of action of MPACs is more complex than chelators and more similar to metal chaperones [129].

Clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) is a small hydrophobic molecule that can cross the BBB and has moderate affinity for copper and zinc while simultaneously acting as their bidentate ligand [45]. Oral administration of CQ reduced the Aβ burden in the brains of Tg2576 transgenic mice by 49% and improved cognitive performance [129]. CQ also significantly decreased plasma Aβ1-42 concentrations and decreased cognitive deterioration in patients with moderate AD [130]. Furthermore, CQ significantly reduced the loss of SN neurons in mouse models of PD induced by 6-hydroxydopamine (6-OHDA) or MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [131]. CQ also attenuated neuropathological symptoms in the R6/2 mouse model, an animal model of HD, including HTT accumulation and brain atrophy, and improved motor function [132]. CQ attenuated demyelination, microglial activation, and enhanced autophagy in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), one of the most commonly used animal models of MS [133]. As a second-generation MPAC, PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) is a more effective copper/zinc ionophore than CQ and has higher solubility and BBB permeability [43]. PBT2 significantly reduced the phosphorylated tau and Aβ burden levels in the brain of AD model mice, which effectively improved their synaptic function and learning and memory ability [134]. A clinical trial also indicated that PBT2 markedly reduced CSF Aβ1-42 levels and improved cognitive performance in AD patients [129]. PBT2 has a high affinity for Aβ protein. It exerts anti-AD effects by regulating the concentration of metal ions in the brain, especially by effectively removing copper and zinc ions from Aβ [128]. Furthermore, PBT2 significantly improved motor function and prolonged lifespan in R6/2 mice and also decreased paralysis in C. elegans overexpressing an extended polyQ tract [63]. Another clinical trial demonstrated that PBT2 reduced the copper-dependent conversion of mHTT monomers to toxic oligomers [132]. In addition, PBT434 is a novel MPAC with a high affinity for copper, which prevented α-syn accumulation, and protected nigrostriatal dopaminergic circuitry and motor function in animal models of PD [131].

5.2 Copper Chelators

Copper chelators are often used to facilitate the excretion of excess copper from the body. DPA, a copper chelator that cannot cross the BBB and has a high affinity for copper ions, ameliorated oxidative stress in AD patients but did not affect cognitive decline [135]. DPA mobilizes copper from the liver and other sites and promotes its excretion into the urine [136], thereby reversing hepatic, neurologic, and psychiatric manifestations in most WD patients [9]. Compared to DPA, the combination of dimercaptosuccinic acid (DMSA) and zinc significantly improved neurologic symptoms in patients with WD [93]. Trientine has a polyamine structure that chelates copper by forming stable complexes with the four constituent nitrogens in a planar ring. It has similar effects to DPA but has fewer side effects and lower risks of neurological deterioration, making it an alternative to DPA for patients who are intolerant to it [90]. Tetrathiomolybdate (TTM) has a lower rate of neurological deterioration (<5%) compared to DPA (50%) and trientine (<20%) [136]. It works through a unique mechanism by forming a stable tripartite complex with copper and protein [98]. In addition, TTM has the advantage of rapid onset, requiring only a few weeks of treatment to restore normal copper balance, and does not increase serum-free copper. In contrast, other copper chelators or zinc take several months [43]. TTM also significantly reduced spinal cord copper ion levels, slowed disease progression, and prolonged lifespan in SOD1G93A mice, exhibiting approximately twice the efficacy of riluzole [85]. Furthermore, combined treatment with CuCl2 and the lipophilic copper chelator sodium dimethyldithiocarbamate (DMDTC) significantly increased brain copper content and extended lifespan in MD model mice [102]. PET studies with 64Cu indicated that pretreatment of MD model mice with the lipophilic chelator disulfiram increased copper transport to the brain and decreased copper uptake by the kidneys. Combined treatment of copper and disulfiram also ameliorated brain copper deficiency [137]. Zhao et al. designed a novel Cu2+-specific chelator named TDMQ20, which completely reversed cognitive and behavioral impairments in three different mouse models simulating the early and late stages of AD and inhibited oxidative stress catalyzed by copper-amyloid complexes in the mouse cortex [138].

5.3 Copper Supplements, Zinc Salts, and Other Medications

Early parenteral administration of copper-histidine significantly alters the progression of MD, although this approach does not ultimately cure the disease [139]. Zinc preparations are the treatment of choice for WD patients with neurological symptoms and are also effective as maintenance therapies. Unlike chelators, zinc inhibits intestinal copper absorption by inducing MTs in enterocytes and the liver. Zinc intake can increase by 25-fold the expression of MT, which is tightly bound to copper and subsequently shed through the feces, thus preventing copper from entering the bloodstream [140, 141]. Zinc preparations mainly include zinc acetate, zinc sulfate, and zinc gluconate [136]. CuII(gtsm) reduced the abundance of Aβ trimer and phosphorylated tau in APP/PS1 mice, decreased the activity of glycogen synthase kinase-3β (GSK-3β), which mediates neurotoxicity, and ultimately reversed cognitive deficits. In addition, CuII(gtsm) also reduced Aβ levels in APP-CHO cells [142]. The positron emission tomography agent CuII(atsm) selectively localizes to the striatum of PD patients, preventing dopaminergic neuron loss and improving motor impairment. Furthermore, it may also exert a protective effect by modulating copper transmission, copper protein activity, and iron metabolism protein expression. CuII(atsm) restored motor and intestinal dysfunction induced by MPTP and neuronal subpopulations in the myenteric plexus [143]. Furthermore, CuII(atsm) also exerted neuroprotective effects by rescuing nigral cell loss [144], inhibiting α-syn nitration and fibrillation [59]. Interestingly, the copper in CuII(atsm) increased the copper content of mutant SOD1 by transferring into it, resulting in an increase in the pool of fully metallated (holo) SOD1, thereby improving motor function and survival in SOD1G37R mice [145]. Oral administration of CuII(atsm) also significantly increased SOD1 activity in SOD1G93A mice, delayed the onset of paralysis and prolonged lifespan, possibly due to its ability to readily cross the BBB and promote CCS-dependent activation of mutant SOD1 [146]. In addition, CuII(atsm) is an anti-nitrosative agent that exerts a protective effect against ALS neurodegeneration by counteracting protein nitration [29]. The copper ionophore elesclomol has recently been reported to deliver copper to mitochondria and elevate CCO levels in the brain to alleviate detrimental neurodegenerative changes and improve survival in the mottled-brindled mouse, a murine model of severe MD [147].

6 POTENTIAL NATURAL COMPOUNDS FOR REGULATING COPPER HOMEOSTASIS

6.1 Luteolin

Luteolin is a plant flavonoid extracted from Elsholtzia rugulosa (Labiatae) that exhibits several biological effects, including antioxidant, anti-inflammatory, and anti-amnesia. Luteolin plays a neuroprotective role in neurodegenerative diseases and traumatic brain injury (TBI) by inhibiting the activation of immune cells, the release of inflammatory mediators, and neuroinflammatory responses [148]. Researchers have established an in vitro model of AD using human neuroblastoma SH-SY5Y cells that overexpress the Swedish mutant form of human APP (APPsw cells), which are induced to become toxic only when copper is added to the culture medium [149]. Luteolin counteracted the toxicity mediated by copper in APPsw cells by down-regulating the expression of amyloid-β protein precursor (AβPP), inhibiting the secretion of Aβ1-42, inhibiting apoptosis, and regulating redox imbalance [150]. Another study indicated that the coordination and transfer of Cu2+ significantly increased the free radical scavenging efficiency and antioxidant activity of luteolin [151].

6.2 Apigenin

Apigenin is a less toxic flavonoid derived from herbs such as Carduus crispus and Elsholtzia rugulosa [152]. It has biological effects such as antioxidant, anticancer, neuroprotective, and free radical scavenging. Apigenin antagonized copper-mediated Aβ neurotoxicity in APPsw cells and exerted neuroprotective effects mainly by alleviating oxidative stress, inhibiting ROS-induced p38 mitogen-activated protein kinases (p38 MAPK) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) signaling pathways, inhibiting apoptosis and protecting mitochondrial function [153]. Interestingly, luteolin, apigenin, and rosmarinic acid (RA) can be simultaneously isolated from the copper-tolerant plant Elsholtzia splendens, a native Chinese herb of the Labiatae family grown in copper deposits in China [154].

6.3 Vitegnoside

Vitegnoside is a flavonoid derived from Vitex negundo, which is used as a folk medicinal plant in Asian countries such as China and Japan and has biological activities such as antioxidant, anti-inflammatory, and anti-osteoporosis. By inhibiting the p38 MAPK/JNK signaling pathway, vitegnoside attenuated neuronal injury, inflammation, and mitochondria-mediated apoptosis in copper-induced APPsw cells [155].

6.4 Quercetin

Quercetin is a natural plant flavonol with a polyphenol structure, mainly derived from red onion, cranberry, and blueberry. It also exists in herbal plants such as Hypericum perforatum, Ginkgo biloba, and elderberry. Quercetin has biological activities such as antioxidant, anti-ischemic, anti-inflammatory, and anti-cancer, and is widely used in the treatment of neurological disorders, tumors, and cardiovascular diseases [156-158]. For example, studies have shown that it exerts significant neuroprotective effects in TBI [158]. Quercetin significantly inhibited the formation of OH- in the Fenton reaction by chelating with copper through Electron Paramagnetic Resonance (EPR) spin-trapping experiments. In addition, the Cu2+-quercetin complex exhibited stronger free radical scavenging activity [159]. Quercetin inhibited copper-induced oxidative stress in SH-SY5Y cells and attenuated copper-induced apoptosis and ER stress by upregulating autophagosome-bound microtubule-associated protein light chain-3 II (LC3II) to regulate autophagy [160]. It was discovered in another study that quercetin also exerted neuroprotective effects on copper-induced P19 neurons by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and ERK1/2 signaling pathways [161]. In addition, quercetin enhanced the induction of MT by copper in a dose-dependent manner, consistent with the mechanism of action of zinc preparations for treating WD, revealing the remarkable potential of quercetin in controlling copper toxicity in WD [162].

6.5 Epigallocatechin Gallate (EGCG)

The main bioactive components of green tea (Camellia sinensis) are catechins, of which EGCG is the most abundant. EGCG is a flavone-3-ol polyphenol with a remarkable ability to scavenge free radicals and particularly prominent anticancer effects [163, 164]. EGCG exerts neuroprotective effects in models of AD, PD, ALS, and ischemic stroke [165]. EGCG reduced Cu2+-induced ROS production in α-syn-transduced PC12 cells, inhibited the overexpression and fibrillation of α-syn, and protected cells from Cu2+-mediated toxicity. In addition, EGCG also inhibited the Cu2+-induced conformational transition of α-syn to β-sheet by coordinating with Cu2+ to form a Cu2+-EGCG complex, and this complex also inhibited Cu2+-induced α-syn fibrillation [166].

6.6 Myricetin

Myricetin is a natural flavonoid extracted from several herbs, such as Ginkgo biloba and St. John’s Wort, which has therapeutic effects on CNS diseases such as AD, PD, and depression [167-169]. Myricetin inhibited the formation of Aβ aggregates by competing with Aβ for binding metal ions and reduced the neurotoxicity of Aβ in Cu2+ and Zn2+-treated human neuroblastoma SK-N-BE(2)-M17 cells (M17) [170, 171].

6.7 Curcumin

Curcumin is a hydrophobic polyphenol in the herbal plant Curcuma longa (Zingiberaceae) with anti-inflammatory, antioxidant, and antidepressant bioactivities [172], and is widely used in the treatment of AD, depression, cancer, and various inflammatory diseases [173]. Curcumin reduced anxiety caused by subchronic copper toxicity by modulating serotonin and improved spatial learning and memory abilities [174]. Furthermore, liposome-encapsulated curcumin (LEC) significantly attenuated copper-induced liver injury and liver fibrosis in an ATP7B-knockout WD mouse model [175]. Dendrosomal nano-curcumin (DNC) exerted antioxidant and anti-inflammatory effects in the EAE model of MS, also resisted cuprizone-induced toxic demyelination, and effectively protected myelinating cells [176]. Low doses of curcumin inhibited Cu2+-induced oxidative stress and reversed neuronal damage in rat cortical neurons [177]. Furthermore, nano-curcumin has similar activity to curcumin but has higher solubility and stability. They attenuated CuSO4-induced neurotoxicity by alleviating oxidative damage, apoptosis, and inflammatory responses and modulating the Akt/GSK-3β pathway [178]. It has been demonstrated that curcumin can protect the dopaminergic system and motor performance against subchronic and acute copper toxicity [144, 179], which is consistent with the neuroprotective effects exerted by AEAAG against copper toxicity. In vitro studies showed that curcumin attenuated copper-induced neurotoxicity in SH-SY5Y cells by inhibiting mitochondrial apoptosis and oxidative stress [171]. It also significantly inhibited Cu2+-induced upregulation of APP and BACE1 transcript levels in PC12 cells [180].

6.8 Rutin

Rutin is a glycoside composed of the flavonol aglycone quercetin and disaccharide rutinose derived from the herbal plant Ruta graveolens and fruits such as oranges, grapes, and berries [181]. Like most polyphenols, rutin crosses the BBB and exhibits antioxidant properties. Rutin ameliorated copper-induced brain damage, including perforated laminae of the cerebral cortex and neuronal degeneration, by alleviating oxidative stress and neuroinflammation [182].

6.9 Resveratrol

Resveratrol is a natural polyphenol compound present in various plants, including rhizoma polygonum cuspidatum, grapes, pine nuts, and peanuts, and also rich in red wine. In addition to its antioxidant and anti-inflammatory properties, it has been shown to improve cerebral ischemic injury and cardiovascular disease [183, 184]. Resveratrol modulated plasma copper and zinc levels and affected oxidative stress and antioxidant status in copper-deficient rats [185]. In addition, it attenuated CuSO4-induced senescence by up-regulating autophagy to regulate cellular proteostasis [186]. Resveratrol also modulated the homeostasis of copper and zinc levels in the blood and improved oxidative stress in a rat model of Type 2 diabetes [187] and aluminum exposure [188]. Dietary supplementation with resveratrol improved plasma copper and zinc levels, antioxidant status, lipid metabolism, and vasodilation in copper-induced (CuNPs/CuCO3) mice [189]. Another study found that resveratrol effectively alleviated oxidative stress induced by copper oxide nanoparticles (CuONPs) and liver and kidney damage [190].

CONCLUSION

A growing body of evidence, including preclinical studies in vivo and in vitro, meta-analyses, and large epidemiological studies, suggests that one of the potential risk factors for neurodegenerative diseases is an age-related imbalance in metal homeostasis. Copper is an important biologic metal, present in high micromolar concentrations in cortical tissue and released as a free ion during neural activity. The trace element copper plays a vital role in maintaining the body's growth, development, and metabolic homeostasis. Excessive copper loading leads to oxidative damage through the Fenton reaction, while copper deficiency disrupts its normal physiological function by affecting copper enzyme activity. Abnormal copper metabolism or distribution may lead to a variety of diseases, with a particular link to neurodegenerative diseases. In the past few decades, people's average life expectancy has gradually increased, and the incidence of age-related neurodegenerative diseases has been rising globally, imposing a heavy burden on society and patients. Currently, drugs that aim to regulate copper balance are mainly a series of MPACs, copper chelators, copper supplements, and zinc salts. However, these treatments can only temporarily alleviate the disease's symptoms to a certain extent but cannot prevent or reverse its progression. In addition, many drugs have limitations, including limited therapeutic efficacy, severe side effects, and poor compliance. For example, chronic or excessive intake of CQ resulted in severe deficiencies of copper, zinc, and iron and subacute myelo-optic neuropathy (SMON), which was previously prevalent in the Japanese population [191]. The early adverse effects of DPA include fever, rash, proteinuria, lymphadenopathy, and thrombocytopenia, while the late side effects include nephrotoxicity and bone marrow suppression [90]. TTM also has side effects such as anemia, leukopenia, and elevation of transaminase enzymes [136]. Even though zinc salts have been reported to cause fewer side effects, mainly gastric problems [192], they are very slow-acting, and free copper is not expected to be controlled within 6-12 months, during which time the disease may continue to progress [98]. Furthermore, finding the right timing for treatment is also challenging. Copper-histidine subcutaneous injections are effective depending on the maturity of the BBB and residual copper transport activity, with the maturity of the BBB determining whether the copper is captured or delivered to the neurons. Therefore, copper injection has shown promising clinical efficacy in neonates with immature BBB but limited therapeutic effect in patients older than two months old [137]. Furthermore, the absence of overt clinical signs and reliable biochemical markers makes it difficult to distinguish neonates with MDs from healthy neonates [193]. Therefore, there are significant difficulties with newborn screening and early treatment of MD. Notably, both CQ and PBT2 failed in phase II trials, possibly due to their inability to distinguish copper bound to essential metalloproteins from toxic copper bound to Aβ [138]. DPA cannot directly alter intracellular copper homeostasis since it is difficult to cross the BBB and has limited therapeutic effect [194].

In addition to drugs to treat neurodegenerative diseases, gene therapy is also promising. For example, silencing CTR1 inhibited α-syn aggregation caused by intracellular copper accumulation [195], overexpression of MT-3 significantly reduced polyQ aggregation and toxicity in an HD cell model [64], and the addition of ATP7A gene targeting the brain via an AAV-5 vector increased survival in mouse models of MD [15]. It is also worth noting that copper overload has been found in many neurodegenerative diseases. In contrast, the copper chelator TTM effectively inhibits cuproptosis, and the metabolite α-lipoic acid in the cuproptosis pathway also exhibited substantial potential in both in vitro and in vivo models of WD [196]. Therefore, it is reasonable to speculate that cuproptosis may play an important role in the progression of neurodegenerative diseases. Cuproptosis is likely to become another potential critical therapeutic target for neurodegenerative diseases. In addition, the risk of excessive copper exposure can also be reduced by installing reverse osmosis devices on faucets, avoiding copper-containing supplements, reducing meat intake appropriately, and avoiding occupational activities with long-term exposure to metals [13, 197]. Although some existing drugs can reduce pathological copper deposition to a certain extent, they cannot restore normal copper metabolism. To date, liver transplantation remains the only option for permanently restoring normal copper metabolism [198]. However, the shortage of donors and the need for lifelong immunosuppressive medication significantly limit its application [199]. Therefore, developing novel, safe, effective drugs remains an urgent problem, and modulation targeting copper levels remains a promising option. The drug should at least meet some basic requirements, including the ability to cross the BBB, sound therapeutic effects, no or only minimal toxic side effects, and not chelating other essential trace metals.

Natural compounds represent a valuable cultural legacy of humanity. Numerous studies have pointed out the neuroprotective effects of many natural compounds. For example, icariin is a flavonoid compound derived from the genus Epimedium, which effectively improved the neuroethology function of TBI rats and reduced neuroinflammation and pathological injury [200]. Many medicinal plants and their natural components have antioxidant, free radical scavenging, and neuroprotective pharmacological properties and have a remarkable effect in preventing copper-induced neurotoxicity. Dracocephalum moldavica L. (Labiatae) is a traditional herbal medicine mainly produced in northern China and has substantial medicinal value for diseases such as hypertension, coronary heart disease, and hepatitis. In copper-injured APPsw cells, total flavonoid extracts of Dracocephalum moldavica L. reduced copper-induced toxicity by modulating redox imbalance, APP expression, Aβ1–42 content, and the extracellular signal-regulated kinase (ERK)/ cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway [149]. Aloe arborescens Miller (Liliaceae) has various pharmacological effects, including antioxidant, anti-inflammatory, and anti-cancer properties. It was found that its extract, Aloe arborescens gel (AEAAG), reversed locomotor deficits in rats with acute copper toxicity. Furthermore, AEAAG reversed the loss of tyrosine hydroxylase (TH) expression within SNpc, ventral tegmental area (VTA), and the subsequent striatal outputs. The neuroprotective effect of AEAAG against copper-induced dopaminergic neurotoxicity reveals its potential in preventing heavy metal neurotoxicity and treating PD [201]. EGb761 is a standardized extract derived from Ginkgo biloba leaves, containing mainly ginkgo flavonoid glycosides, terpene trilactones, ginkgolides, and bilobalide, which has neuroprotective effects against AD, PD, and subarachnoid hemorrhage (SAH) [202]. Rojas et al. used EGb761 to pretreat MPP+ (1-methyl-4-phenylpyridinium, the active metabolite of MPTP)-induced PD mouse model. They found that copper content in the corpus striatum of mice treated with MPP+ was significantly decreased, whereas copper content in the midbrain and hippocampus increased significantly. EGb761 pretreatment prevented changes in copper content in these brain regions, suggesting that EGb761 blocked MPP+ neurotoxicity by modulating copper homeostasis in the brain [203]. Kaempferia galanga L. (Zingiberaceae) has pharmacological activities such as antimicrobial, anti-inflammatory, analgesic, sedative, and antiparasitic [173], and kaempferol is a flavonoid mainly derived from its rhizome [204], which exerted a certain protective effect on DNA damage mediated by singlet oxygen, OH- and superoxide radical anions. In comparison to free kaempferol, Cu-kaempferol complexes exhibited stronger free radical scavenging effects. The antioxidant properties of kaempferol under copper-Fenton conditions suggest that it may exert neuroprotective effects in neurological diseases involving disturbances in copper metabolism [205]. RA is a polyphenolic compound first isolated from rosemary. It exists in many medicinal herbs of the Boraginaceae family and Nepetoideae sub-family of the Lamiaceae family, including Perilla frutescens and Melissa officinalis [206]. RA exerted a protective effect by interfering with the anomalous and toxic Cu2+-Aβ interaction. Furthermore, RA binds Cu2+ and mediates the interaction between Aβ and the paramagnetic ion. It also weakly interacts with Aβ and reduces its mediated cytotoxicity [207]. Astragaloside IV (AS-IV) is a triterpenoid saponin present in the root of Astragalus membranaceus, which has anti-apoptosis, anti-oxidation, and anti-inflammatory properties, and exhibits neuroprotective effects on AD, PD, and cerebral ischemia [208]. Another study established an in vivo specific Cu(I) reporting system, PMT1F-EGFP reporter, and found that AS-IV significantly increased intracellular copper ions, even in the low-copper microenvironment [209]. In addition to natural herbs, synthetic herbal derivatives, such as naringin, have shown great potential in the treatment of neurodegenerative diseases. Naringin is a natural flavonoid in citrus fruits such as Citrus aurantium L. (Fructus aurantia) and Drynaria fortunei (Kunze) J. Sm [210-212]. A study has synthesized N,N’-1,10-bis(naringin) triethylenetetraamine bis-Schiff bases as a Cu2+ chelator. It effectively inhibited Cu2+-induced Aβ1-42 aggregations and reduced the toxicity mediated by Aβ1-42-Cu2+ in PC12 cells by inhibiting ROS production and enhancing superoxide dismutase (SOD) activity [213]. The design and synthesis of natural compounds and metal-chelating agents have also opened up a new field for developing new drugs. A novel multi-target compound has been synthesized by combining resveratrol with the pharmacophore moiety of CQ. This hybrid combines the characteristics of resveratrol and CQ simultaneously. It can cross the BBB, significantly inhibit Cu2+-induced Aβ aggregation, and could also control the production of OH- triggered by Cu2+, exhibiting excellent multi-target-directed ligand (MTDL) properties [214, 215]. Natural compounds are important sources for drug development and offer promising applications for the prevention and treatment of neurodegenerative diseases. There is great potential for the future development of new drugs for the treatment of neurodegenerative diseases based on the regulation of copper metabolism from natural compounds, and it deserves in-depth study.

ACKNOWLEDGEMENTS

Declared none.

LIST OF ABBREVIATIONS

AD Alzheimer's Disease

AEAAG Aloe Arborescens Gel

Akt Protein Kinase B

ALS Amyotrophic Lateral Sclerosis

ApoE Apolipoprotein E

ApoE4 Apolipoprotein E4

APP Amyloid Precursor Protein

AS-IV Astragaloside IV

ATOX1 Antioxidant Protein 1

ATP7A P-type Copper-transporting Atpase α

ATP7B P-type Copper-transporting Atpase β

Aβ Amyloid β

AβPP Amyloid-β Protein Precursor

α-syn α-synuclein

BACE1 β-site APP Cleaving Enzyme 1

BBB Blood-brain Barrier

BCB Blood-cerebrospinal Fluid Barrier

BDNF Brain-derived Neurotrophic Factor

CAG Cytosine-Adenine-Guanine

CCO Cytochrome C Oxidase

CCS Copper Chaperone for Superoxide Dismutase

CJD Creutzfeldt-Jakob Disease

CNS Central Nervous System

COX17 Copper Chaperone for CCO

Cp Ceruloplasmin

CQ Clioquinol

CREB Camp Response Element-binding Protein

CSF Cerebrospinal Fluid

CTR1 Copper Transporter 1

Cu Copper

Cu/Zn SOD or SOD1 Copper/Zinc-superoxide Dismutase

Cu+ Organic Copper

Cu2+ Inorganic Copper

CuONPs Copper Oxide Nanoparticles

DMDTC Dimethyldithiocarbamate

DMSA Dimercaptosuccinic Acid

DMT1 Divalent Metal Transporter 1

DNA Deoxyribonucleic Acid

DNC Dendrosomal Nano-curcumin

DPA D-penicillamine

EAE Experimental Autoimmune Encephalomyelitis

EGCG Epigallocatechin Gallate

EPR Electron Paramagnetic Resonance

ER Endoplasmic Reticulum

ERK Extracellular Signal-regulated Kinase

FALS Familial ALS

Fe-S Iron-sulfur

GPI Glycosylphosphatidylinositol

GSH Glutathione

GSK-3β Glycogen Synthase Kinase-3β

H2O2 Hydrogen Peroxide

HD Huntington's Disease

HTT Huntingtin

JNK c-Jun N-terminal Kinase

LC3II Microtubule-associated Protein Light Chain-3 II

LDH Lactate Dehydrogenase

LEC Liposome-encapsulated Curcumin

LRP1 Low-density Lipoprotein Receptor-related Protein-1

MCI Mild Cognitive Impairment

MD Menkes Disease

mHTT Mutant Huntingtin

MOG Myelin Oligodendrocyte Glycoprotein

MPACs Metal-Protein Attenuating Compounds

MPP+ 1-Methyl-4-phenylpyridinium

MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS Multiple Sclerosis

MT Metallothionein

MTDL Multi-target-directed Ligand

NMDARs N-methyl-D-aspartate Receptors

Non-Cp-Cu Non-ceruloplasmin-bound Copper

6-OHDA 6-Hydroxydopamine

O2- Superoxide Anions

OH- Hydroxyl Radicals

p38 MAPK P38 Mitogen-activated Protein Kinases

PBT2 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline

PD Parkinson's Disease

PI3K Phosphatidylinositol-3-kinase

polyQ Polyglutamine

PrP Prion Protein

RA Rosmarinic Acid

RNS Reactive Nitrogen Species

ROS Reactive Oxygen Species

SAH Subarachnoid Hemorrhage

SALS Sporadic ALS

SAPK Stress-activated Protein Kinase

SCJD Sporadic CJD

SMON Subacute Myelo-optic Neuropathy

SN Substantia Nigra

SNpc Substantia Nigra Pars Compacta

SOD Superoxide Dismutase

STEAP Six Transmembrane Epithelial Antigen of The Prostate

Tau Tubulin-associated Unit

TBI Traumatic Brain Injury

TCA Tricarboxylic Acid

TCM Traditional Chinese Medicine

TGN Trans-golgi Network

TH Tyrosine Hydroxylase

TNF-α Tumor Necrosis Factor-α

TTM Tetrathiomolybdate

VTA Ventral Tegmental Area

WD Wilson's Disease

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

This work was supported by the National Natural Science Foundation of China (Grant no. 81973918, 82274616), the Key laboratory project of colleges and universities in Guangdong Province (Grant no. 2019KSYS005), and the Guangdong province science and technology plan international cooperation project (Grant no. 2020A0505100052).

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

Fig. (1) Schematic diagram of the mechanism of cellular copper uptake, distribution, and metabolism. Extracellularly, Cu2+ is reduced to Cu+ by reductases such as the six transmembrane epithelial antigen of the prostate (STEAP) and then transported into the cell through the membrane protein CTR1 [27, 28], and delivered to specific sites by several copper transporters, including ATOX1, CCS, and COX17. In addition, DMT1 on the plasma membrane can directly incorporate Cu2+ into the cell [13]. ATOX1 transports copper to ATP7A and ATP7B located in the trans-Golgi network (TGN) and subsequently binds to various copper-dependent enzymes [12]. To facilitate the excretion of excess intracellular copper, ATPases are translocated from the TGN to the plasma membrane when intracellular copper levels are elevated [28]. CCS incorporates copper into cytoplasmic SOD1, which catalyzes the dismutation of O2.− into H2O2 and molecular oxygen, protecting cells from free radical damage [28]. COX17 transports copper into COX11, SCO1, and SCO2 in the mitochondria and subsequently binds to CCO for its metallation and activation [29]. In addition, intracellular copper also binds to glutathione (GSH) and mediates copper transport to metallothionein (MT) for storage [26].

Fig. (2) Chemical structures of several drugs targeting copper for the treatment of neurodegenerative diseases. CQ is used in the treatment of AD, PD, HD, and MS; PBT2 is used in the treatment of AD and HD; PBT434 is used in the treatment of PD; DPA is used in the treatment of AD and WD; Trientine, DMSA and zinc acetate are used in the treatment of WD; TTM is used in the treatment of ALS and WD; Copper-histidine and elesclomol are used in the treatment of MD; CuII (atsm) is used in the treatment of PD and ALS.

Table 1 Summary of the copper-related genes, pathogenesis, and changes in copper homeostasis in neurodegenerative diseases.

Diseases	Genes	Copper-related Pathogenesis	Changes in Copper Homeostasis	References	
AD	ApoE4, ATP7B	Copper promotes Aβ and tau aggregation, oxidative damage, and neuroinflammation and inhibits Aβ clearance by affecting the
metabolism of BACE1, APP, Aβ, tau, and LRP1.	Serum Cu
Brain ceruloplasmin
Brain Cu
(while in Aβ↑)	↑
↑
↓	[13, 26, 40-46, 48-55, 126]	
PD	-	Copper promotes α-syn aggregation, affects redox homeostasis, and causes damage to dopaminergic neurons by binding to α-syn and regulating iron metabolism.	Caudate nucleus Cu
SN Cu	↓
↓	[46, 59, 61]	
HD	-	Copper promotes HTT aggregation and affects its conformation, increases the aggregation and toxicity of polyQ, and inhibits LDH activity to result in neurodegeneration.	Brain Cu (particularly in the putamen and SN)	↑	[45, 64-69]	
ALS	SOD1	Mutations in SOD1 result in defective binding to Cu and protein misfolding, disrupting intracellular copper homeostasis and resulting in toxicity.	Spinal cord Cu
Motor cortex Cu
Serum Cu and ceruloplasmin	↑
↑
↓	[27, 45, 72-75, 78-83, 85, 127]	
WD	ATP7B	Defective ATP7B function results in the inability of copper to be incorporated into ceruloplasmin, the dysfunction of copper excretion into the bile, and the disruption of mitochondrial function by the excess copper load.	Liver, brain and cornea Cu
Urine Cu
Serum ceruloplasmin	↑
↑
↓	[9, 86-90, 93-98]	
MD	ATP7A	Mutations in the ATP7A gene affect copper transport across the intestinal mucosa and the BBB, resulting in decreased activity of a series of copper-dependent enzymes and systemic copper deficiency.	Intestine, kidney Cu
Serum, liver, and brain Cu
Plasma ceruloplasmin	↑
↓
↓	[99, 102-105]	
Prion diseases	-	Copper binding to PrPC promotes the conformational transition of PrPC to PrPSc, increases protease resistance and protein infectivity, and Cu2+ is also involved in the aggregation of human PrP.	Brain Cu	↓	[82, 107, 115, 116, 122]	
MS	-	Dysregulation of copper homeostasis causes demyelination by astrocytes.	Serum Cu
CSF Cu	↑
↑	[24, 125]	

Table 2 Summary of in vitro studies of natural compounds with the potential to improve neurodegenerative diseases by modulating copper metabolism.

Compounds	Chemical Structure	Models	Dosage	Pharmacological Effects	Molecular Mechanisms	References	
Luteolin		Copper-induced APPsw cells	1, 10 μM for 24 h	Increase cell viability, inhibit Aβ secretion and apoptosis, regulate redox imbalance, and protect mitochondrial function.	Downregulate AβPP expression; reduce intracellular ROS production; enhance SOD activity; reverse mitochondrial membrane potential dissipation; inhibit the activities of caspase-3 and caspase-9.	[150]	
Apigenin		Copper-induced APPsw cells	0.1, 1, 10 μM for 24 h	Alleviate oxidative stress, inhibit neuronal apoptosis, increase neuronal viability, relieve mitochondrial membrane dissipation and neuronal nuclear condensation.	Increase GSH levels; enhance GSH-Px and SOD activities; reduce ROS production; inhibit ROS-induced p38 MAPK-MK2-Hsp27 and SAPK/JNK signaling pathway; inhibit cytochrome c release and caspase-3, caspase-9
activity.	[153]	
Vitegnoside		Copper-induced APPsw cells	0.3, 1, 3, 10, 30 μM	Improve cell viability, protect mitochondrial function, inhibit inflammation and mitochondrial-mediated apoptosis.	Inhibit cytochrome c release; reduce caspase-3 and caspase-9 activation; reduce Bax/Bcl2 ratio; inhibit p38 MAPK and JNK signaling pathways.	[155]	
Quercetin		CuSO4-induced SH-SY5Y cells	50 nm for 4 h	Improve cell viability, inhibit oxidative stress and ER stress, regulate autophagy to inhibit apoptosis.	Inhibit intracellular ROS levels; restore mitochondrial membrane potential; upregulate Bcl2 and LC3II expression; downregulate Bax, cleaved PARP, cleaved caspase 3, cytochrome c, p53, XBP1, PERK, NRF2, CHOP, BiP, Bim, caspase
12 expression and α-syn levels.	[160]	
CuSO4-induced P19 neurons	3, 30, 150 μM for 24 h	Improve neuronal survival, inhibit oxidative injury.	Inhibit ROS production, chromatin condensation
and decreased caspase-3/7 activity; reduce increased PUMA expression, upregulate NME1; regulate PI3K/Akt and ERK1/2 signaling.	[161]	
EGCG		α-syn gene transduced PC12 cells	1, 5, 10, 20, 30 µM for 48 h or 1, 2, 5, 10, 20 µM for 24 h	Inhibit the production of α-syn, reduce cell death and oxidative stress.	Hinder α-syn conformation transition and ROS production; reduce α-syn overexpression and fibrillation.	[166]	
Myricetin		Aβ, CuCl2 and ZnCl2 induced SK-N-BE(2)-M17 cells	50 μM for 4 or 24 h, 20 μM for 24 h	Inhibit the formation of Aβ aggregates, reduce copper-induced Aβ cytotoxicity, and improve the cell survival rate.	Compete with Aβ to bind copper ions.	[170]	
Curcumin		CuSO4-induced SH-SY5Y cells	1, 2.5, 5 μM for 3 h	Inhibit oxidative stress and mitochondrial apoptosis.	Downregulate ROS, MDA levels, and Bax/Bcl2 ratio; increase SOD and CAT activities; attenuate mitochondrial membrane potential decline and nuclear translocation of cytochrome c; upregulate pro-caspase-3, pro-caspase-9, and PARP1 levels.	[171]	

Table 3 Summary of in vivo studies of natural compounds with the potential to improve neurodegenerative diseases by modulating copper metabolism.

Compounds	Chemical Structure	Models	Dosage	Pharmacological Effects	Molecular Mechanisms	References	
Curcumin		CuSO4-induced Wistar rats	80 mg/kg orally for 7 days	Attenuate oxidative injury, apoptosis, and inflammation.	Downregulate brain levels of MDA, NF-κB p65, TNF-α,
IL-6, Bax, p53, and caspase-3; increase brain levels of GSH, SOD, CAT, Bcl-2, and BDNF; reduce DNA fragmentation; increase brain AKT and GSK-3β phosphorylation.	[178]	
Copper-induced subchronic copper intoxication in Wistar rats	30 mg/kg orally for 6 weeks	Improve locomotor performance.	Reverse the loss of GFAP and TH expression in SNpc, VTA, and the subsequent striatal outputs.	[179]	
Copper-induced acute copper intoxication in Wistar rats	30 mg/kg orally for 3 days	Enhance locomotor performance.	Reverse the loss of TH expression in SNpc, VTA, and the subsequent striatal outputs.	[144]	
Rutin		CuSO4-induced Wistar rats	100 mg/kg orally for 7 weeks	Antioxidant, inhibit inflammation.	Increase SOD, CAT, GPx, GSH, and AchE activities; decrease MPO activity, NO levels, COX-2, and iNOS expression.	[182]	
Resveratrol		CuCO3/CuNPs-induced Wistar rats	500 mg/kg in diet orally for 8 weeks	Improve vascular responses, the lipid profile, and the antioxidant mechanism.	Increase plasma SOD activity and zinc levels; decrease plasma Cu, CAT, GPx, LDL-c, LOOH, and MDA levels; decrease fasting blood glucose; regulate vasodilation.	[189]	
CuONPs-induced Wistar rats	60 mg/kg i.g. for 7 days	Improve liver and kidney pathological changes.	Reduce serum TOS, TAC, creatinine, and urea levels; suppress the elevation of ALT and AST levels.	[190]
==== Refs
REFERENCES

1 Hetz C. Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat. Rev. Neurol. 2017 13 8 477 491 10.1038/nrneurol.2017.99 28731040
2 Barnham K.J. Masters C.L. Bush A.I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov. 2004 3 3 205 214 10.1038/nrd1330 15031734
3 Nixon R.A. The role of autophagy in neurodegenerative disease. Nat. Med. 2013 19 8 983 997 10.1038/nm.3232 23921753
4 Ross C.A. Poirier M.A. Protein aggregation and neurodegenerative disease. Nat. Med. 2004 10 S7 Suppl. S10 S17 10.1038/nm1066 15272267
5 Nguyen P.H. Ramamoorthy A. Sahoo B.R. Zheng J. Faller P. Straub J.E. Dominguez L. Shea J.E. Dokholyan N.V. De Simone A. Ma B. Nussinov R. Najafi S. Ngo S.T. Loquet A. Chiricotto M. Ganguly P. McCarty J. Li M.S. Hall C. Wang Y. Miller Y. Melchionna S. Habenstein B. Timr S. Chen J. Hnath B. Strodel B. Kayed R. Lesné S. Wei G. Sterpone F. Doig A.J. Derreumaux P. Amyloid oligomers: a joint experimental/computational perspective on Alzheimer’s disease, Parkinson’s disease, Type II diabetes, and amyotrophic lateral sclerosis. Chem. Rev. 2021 121 4 2545 2647 10.1021/acs.chemrev.0c01122 33543942
6 Arnal N. Castillo O. de Alaniz M.J.T. Marra C.A. Effects of copper and/or cholesterol overload on mitochondrial function in a rat model of incipient neurodegeneration. Int. J. Alzheimers Dis. 2013 2013 1 14 10.1155/2013/645379 24363953
7 Ke Y. Qian Z.M. Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol. 2003 2 4 246 253 10.1016/S1474-4422(03)00353-3 12849213
8 Chen J. Jiang Y. Shi H. Peng Y. Fan X. Li C. The molecular mechanisms of copper metabolism and its roles in human diseases. Pflugers Arch. 2020 472 10 1415 1429 10.1007/s00424-020-02412-2 32506322
9 Russell K. Gillanders L.K. Orr D.W. Plank L.D. Dietary copper restriction in Wilson’s disease. Eur. J. Clin. Nutr. 2018 72 3 326 331 10.1038/s41430-017-0002-0 29235558
10 Kolbaum A.E. Sarvan I. Bakhiya N. Spolders M. Pieper R. Schubert J. Jung C. Hackethal C. Sieke C. Grünewald K.H. Lindtner O. Long-term dietary exposure to copper in the population in Germany – Results from the BfR MEAL study. Food Chem. Toxicol. 2023 176 113759 10.1016/j.fct.2023.113759 37028745
11 Tokuşoǧlu, Ö.; Aycan, Ş.; Akalin, S.; Koçak, S.; Ersoy, N. Simultaneous differential pulse polarographic determination of cadmium, lead, and copper in milk and dairy products. J. Agric. Food Chem. 2004 52 7 1795 1799 10.1021/jf034860l 15053511
12 Zheng W. Monnot A.D. Regulation of brain iron and copper homeostasis by brain barrier systems: Implication in neurodegenerative diseases. Pharmacol. Ther. 2012 133 2 177 188 10.1016/j.pharmthera.2011.10.006 22115751
13 Brewer G. Copper-2 ingestion, plus increased meat eating leading to increased copper absorption, are major factors behind the current epidemic of Alzheimer’s disease. Nutrients 2015 7 12 10053 10064 10.3390/nu7125513 26633489
14 Ruiz L.M. Libedinsky A. Elorza A.A. Role of copper on mitochondrial function and metabolism. Front. Mol. Biosci. 2021 8 711227 10.3389/fmolb.2021.711227 34504870
15 Scheiber I.F. Mercer J.F.B. Dringen R. Metabolism and functions of copper in brain. Prog. Neurobiol. 2014 116 33 57 10.1016/j.pneurobio.2014.01.002 24440710
16 Arredondo M. Núñez M.T. Iron and copper metabolism. Mol. Aspects Med. 2005 26 4-5 313 327 10.1016/j.mam.2005.07.010 16112186
17 Gromadzka G. Tarnacka B. Flaga A. Adamczyk A. Copper dyshomeostasis in neurodegenerative diseases-therapeutic implications. Int. J. Mol. Sci. 2020 21 23 9259 10.3390/ijms21239259 33291628
18 Kaler S.G. ATP7A-related copper transport diseases—emerging concepts and future trends. Nat. Rev. Neurol. 2011 7 1 15 29 10.1038/nrneurol.2010.180 21221114
19 Rasoul A.A. Khudhur Z.O. Hamad M.S. Ismaeal Y.S. Smail S.W. Rasul M.F. Mohammad K.A. Bapir A.A. Omar S.A. Qadir M.K. Rajab M.F. Salihi A. Kaleem M. Rizwan M.A. Qureshi A.S. Iqbal Z.M. Qudratullah. The role of oxidative stress and haematological parameters in relapsing-remitting multiple sclerosis in Kurdish population. Mult. Scler. Relat. Disord. 2021 56 103228 10.1016/j.msard.2021.103228 34492630
20 Tsvetkov P. Coy S. Petrova B. Dreishpoon M. Verma A. Abdusamad M. Rossen J. Joesch-Cohen L. Humeidi R. Spangler R.D. Eaton J.K. Frenkel E. Kocak M. Corsello S.M. Lutsenko S. Kanarek N. Santagata S. Golub T.R. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 2022 375 6586 1254 1261 10.1126/science.abf0529 35298263
21 An Y. Li S. Huang X. Chen X. Shan H. Zhang M. The role of copper homeostasis in brain disease. Int. J. Mol. Sci. 2022 23 22 13850 10.3390/ijms232213850 36430330
22 Law B.Y.K. Wu A.G. Wang M.J. Zhu Y.Z. Chinese medicine: a hope for neurodegenerative diseases? J. Alzheimers Dis. 2017 60 s1 S151 S160 10.3233/JAD-170374 28671133
23 Pei H. Ma L. Cao Y. Wang F. Li Z. Liu N. Liu M. Wei Y. Li H. Traditional Chinese medicine for Alzheimer’s disease and other cognitive impairment: A review. Am. J. Chin. Med. 2020 48 3 487 511 10.1142/S0192415X20500251 32329645
24 De Riccardis L. Buccolieri A. Muci M. Pitotti E. De Robertis F. Trianni G. Manno D. Maffia M. Copper and ceruloplasmin dyshomeostasis in serum and cerebrospinal fluid of multiple sclerosis subjects. Biochim. Biophys. Acta Mol. Basis Dis. 2018 1864 5 1828 1838 10.1016/j.bbadis.2018.03.007 29524632
25 Sheykhansari S. Kozielski K. Bill J. Sitti M. Gemmati D. Zamboni P. Singh A.V. Redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: A review. Cell Death Dis. 2018 9 3 348 10.1038/s41419-018-0379-2 29497049
26 Hung Y.H. Bush A.I. La Fontaine S. Links between copper and cholesterol in Alzheimer’s disease. Front. Physiol. 2013 4 111 10.3389/fphys.2013.00111 23720634
27 Tokuda E. Okawa E. Ono S. Dysregulation of intracellular copper trafficking pathway in a mouse model of mutant copper/zinc superoxide dismutase-linked familial amyotrophic lateral sclerosis. J. Neurochem. 2009 111 1 181 191 10.1111/j.1471-4159.2009.06310.x 19656261
28 Liu Y. Miao J. An emerging role of defective copper metabolism in heart disease. Nutrients 2022 14 3 700 10.3390/nu14030700 35277059
29 Gil-Bea F.J. Aldanondo G. Lasa-Fernández H. López de Munain A. Vallejo-Illarramendi A. Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis. Expert Rev. Mol. Med. 2017 19 e7 10.1017/erm.2017.9 28597807
30 Davies K.M. Hare D.J. Cottam V. Chen N. Hilgers L. Halliday G. Mercer J.F.B. Double K.L. Localization of copper and copper transporters in the human brain. Metallomics 2013 5 1 43 51 10.1039/C2MT20151H 23076575
31 Skjørringe T. Møller L.B. Moos T. Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders. Front. Pharmacol. 2012 3 169 10.3389/fphar.2012.00169 23055972
32 Sweeney M.D. Sagare A.P. Zlokovic B.V. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 2018 14 3 133 150 10.1038/nrneurol.2017.188 29377008
33 Haywood S. Vaillant C. Overexpression of copper transporter CTR1 in the brain barrier of North Ronaldsay sheep: Implications for the study of neurodegenerative disease. J. Comp. Pathol. 2014 150 2-3 216 224 10.1016/j.jcpa.2013.09.002 24172593
34 Hsu H.W. Bondy S.C. Kitazawa M. Environmental and dietary exposure to copper and its cellular mechanisms linking to Alzheimer’s disease. Toxicol. Sci. 2018 163 2 338 345 10.1093/toxsci/kfy025 29409005
35 Ijomone O.M. Ifenatuoha C.W. Aluko O.M. Ijomone O.K. Aschner M. The aging brain: impact of heavy metal neurotoxicity. Crit. Rev. Toxicol. 2020 50 9 801 814 10.1080/10408444.2020.1838441 33210961
36 Madsen E. Gitlin J.D. Copper and iron disorders of the brain. Annu. Rev. Neurosci. 2007 30 1 317 337 10.1146/annurev.neuro.30.051606.094232 17367269
37 Prasad A.N. Ojha R. Menkes disease: What a multidisciplinary approach can do. J. Multidiscip. Healthc. 2016 9 371 385 10.2147/JMDH.S93454 27574440
38 Goedert M. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ tau, and α-synuclein. Science 2015 349 6248 1255555 10.1126/science.1255555 26250687
39 Sinyor B. Mineo J. Ochner C. Alzheimer’s disease, inflammation, and the role of antioxidants. J. Alzheimers Dis. Rep. 2020 4 1 175 183 10.3233/ADR-200171 32715278
40 Squitti R. Pasqualetti P. Dal Forno G. Moffa F. Cassetta E. Lupoi D. Vernieri F. Rossi L. Baldassini M. Rossini P.M. Excess of serum copper not related to ceruloplasmin in Alzheimer disease. Neurology 2005 64 6 1040 1046 10.1212/01.WNL.0000154531.79362.23 15781823
41 Robert A. Liu Y. Nguyen M. Meunier B. Regulation of copper and iron homeostasis by metal chelators: A possible chemotherapy for Alzheimer’s disease. Acc. Chem. Res. 2015 48 5 1332 1339 10.1021/acs.accounts.5b00119 25946460
42 Lovell M.A. Robertson J.D. Teesdale W.J. Campbell J.L. Markesbery W.R. Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol. Sci. 1998 158 1 47 52 10.1016/S0022-510X(98)00092-6 9667777
43 Ejaz H.W. Wang W. Lang M. Copper toxicity links to pathogenesis of Alzheimer’s disease and therapeutics approaches. Int. J. Mol. Sci. 2020 21 20 7660 10.3390/ijms21207660 33081348
44 Deibel M.A. Ehmann W.D. Markesbery W.R. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: Possible relation to oxidative stress. J. Neurol. Sci. 1996 143 1-2 137 142 10.1016/S0022-510X(96)00203-1 8981312
45 Rivera-Mancía S. Pérez-Neri I. Ríos C. Tristán-López L. Rivera-Espinosa L. Montes S. The transition metals copper and iron in neurodegenerative diseases. Chem. Biol. Interact. 2010 186 2 184 199 10.1016/j.cbi.2010.04.010 20399203
46 Loeffler D.A. LeWitt P.A. Juneau P.L. Sima A.A.F. Nguyen H.U. DeMaggio A.J. Brickman C.M. Brewer G.J. Dick R.D. Troyer M.D. Kanaley L. Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res. 1996 738 2 265 274 10.1016/S0006-8993(96)00782-2 8955522
47 Choo X.Y. Alukaidey L. White A.R. Grubman A. Neuroinflammation and copper in Alzheimer’s disease. Int. J. Alzheimers Dis. 2013 2013 1 12 10.1155/2013/145345 24369524
48 Bagheri S. Squitti R. Haertlé T. Siotto M. Saboury A.A. Role of Copper in the onset of Alzheimer’s disease compared to other metals. Front. Aging Neurosci. 2018 9 446 10.3389/fnagi.2017.00446 29472855
49 Zubčić K.; Hof, P.R.; Šimić G.; Jazvinšćak Jembrek, M. The role of copper in tau-related pathology in Alzheimer’s disease. Front. Mol. Neurosci. 2020 13 572308 10.3389/fnmol.2020.572308 33071757
50 Voss K. Harris C. Ralle M. Duffy M. Murchison C. Quinn J.F. Modulation of tau phosphorylation by environmental copper. Transl. Neurodegener. 2014 3 1 24 10.1186/2047-9158-3-24 25671100
51 Singh I. Sagare A.P. Coma M. Perlmutter D. Gelein R. Bell R.D. Deane R.J. Zhong E. Parisi M. Ciszewski J. Kasper R.T. Deane R. Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance. Proc. Natl. Acad. Sci. USA 2013 110 36 14771 14776 10.1073/pnas.1302212110 23959870
52 Busche M.A. Hyman B.T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat. Neurosci. 2020 23 10 1183 1193 10.1038/s41593-020-0687-6 32778792
53 Aaseth J. Skalny A.V. Roos P.M. Alexander J. Aschner M. Tinkov A.A. Copper, iron, selenium and lipo-glycemic dysmetabolism in Alzheimer’s disease. Int. J. Mol. Sci. 2021 22 17 9461 10.3390/ijms22179461 34502369
54 Pal A. Copper toxicity induced hepatocerebral and neurodegenerative diseases: An urgent need for prognostic biomarkers. Neurotoxicology 2014 40 97 101 10.1016/j.neuro.2013.12.001 24342654
55 Pal A. Kumar A. Prasad R. Predictive association of copper metabolism proteins with Alzheimer’s disease and Parkinson’s disease: a preliminary perspective. Biometals 2014 27 1 25 31 10.1007/s10534-013-9702-7 24435851
56 Bloem B.R. Okun M.S. Klein C. Parkinson’s disease. Lancet 2021 397 10291 2284 2303 10.1016/S0140-6736(21)00218-X 33848468
57 Aaseth J. Dusek P. Roos P.M. Prevention of progression in Parkinson’s disease. Biometals 2018 31 5 737 747 10.1007/s10534-018-0131-5 30030679
58 Tolosa E. Garrido A. Scholz S.W. Poewe W. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol. 2021 20 5 385 397 10.1016/S1474-4422(21)00030-2 33894193
59 Montes S. Rivera-Mancia S. Diaz-Ruiz A. Tristan-Lopez L. Rios C. Copper and copper proteins in Parkinson’s disease. Oxid. Med. Cell. Longev. 2014 2014 1 15 10.1155/2014/147251 24672633
60 Wang Q. Luo Y. Ray Chaudhuri K. Reynolds R. Tan E.K. Pettersson S. The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options. Brain 2021 144 9 2571 2593 10.1093/brain/awab156 33856024
61 Gangania M.K. Batra J. Kushwaha S. Agarwal R. Role of iron and copper in the pathogenesis of Parkinson’s disease. Indian J. Clin. Biochem. 2017 32 3 353 356 10.1007/s12291-016-0614-5 28811697
62 Raj K. Kaur P. Gupta G.D. Singh S. Metals associated neurodegeneration in Parkinson’s disease: Insight to physiological, pathological mechanisms and management. Neurosci. Lett. 2021 753 135873 10.1016/j.neulet.2021.135873 33812934
63 Cherny R.A. Ayton S. Finkelstein D.I. Bush A.I. McColl G. Massa S.M. PBT2 reduces toxicity in a c. elegans model of polyQ aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6/2 mouse model of Huntington’s disease. J. Huntingtons Dis. 2012 1 2 211 219 10.3233/JHD-120029 25063332
64 Hands S.L. Mason R. Sajjad M.U. Giorgini F. Wyttenbach A. Metallothioneins and copper metabolism are candidate therapeutic targets in Huntington’s disease. Biochem. Soc. Trans. 2010 38 2 552 558 10.1042/BST0380552 20298220
65 Dexter D.T. Carayon A. Javoy-Agid F. Agid Y. Wells F.R. Daniel S.E. Lees A.J. Jenner P. Marsden C.D. Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 1991 114 4 1953 1975 10.1093/brain/114.4.1953 1832073
66 Scholefield M. Unwin R.D. Cooper G.J.S. Shared perturbations in the metallome and metabolome of Alzheimer’s, Parkinson’s, Huntington’s, and dementia with Lewy bodies: A systematic review. Ageing Res. Rev. 2020 63 101152 10.1016/j.arr.2020.101152 32846222
67 Grubman A. White A.R. Liddell J.R. Mitochondrial metals as a potential therapeutic target in neurodegeneration. Br. J. Pharmacol. 2014 171 8 2159 2173 10.1111/bph.12513 24206195
68 Maung M.T. Carlson A. Olea-Flores M. Elkhadragy L. Schachtschneider K.M. Navarro-Tito N. Padilla-Benavides T. The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB J. 2021 35 9 e21810 10.1096/fj.202100273RR 34390520
69 Fox J.H. Kama J.A. Lieberman G. Chopra R. Dorsey K. Chopra V. Volitakis I. Cherny R.A. Bush A.I. Hersch S. Mechanisms of copper ion mediated Huntington’s disease progression. PLoS One 2007 2 3 e334 10.1371/journal.pone.0000334 17396163
70 Clarke B.E. Patani R. The microglial component of amyotrophic lateral sclerosis. Brain 2020 143 12 3526 3539 10.1093/brain/awaa309 33427296
71 Van Harten A.C.M. Phatnani H. Przedborski S. Non-cell-autonomous pathogenic mechanisms in amyotrophic lateral sclerosis. Trends Neurosci. 2021 44 8 658 668 10.1016/j.tins.2021.04.008 34006386
72 Gellein K. Garruto R.M. Syversen T. Sjøbakk T.E. Flaten T.P. Concentrations of Cd, Co, Cu, Fe, Mn, Rb, V, and Zn in formalin-fixed brain tissue in amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam determined by High-resolution ICP-MS. Biol. Trace Elem. Res. 2003 96 1-3 39 60 10.1385/BTER:96:1-3:39 14716085
73 Kapaki E. Zournas C. Kanias G. Zambelis T. Kakami A. Papageorgiou C. Essential trace element alterations in amyotrophic lateral sclerosis. J. Neurol. Sci. 1997 147 2 171 175 10.1016/S0022-510X(96)05334-8 9106124
74 Barros A.N.A.B. Dourado M.E.T. Jr Pedrosa L.F.C. Leite-Lais L. Association of copper status with lipid profile and functional status in patients with amyotrophic lateral sclerosis. J. Nutr. Metab. 2018 2018 1 7 10.1155/2018/5678698 30116640
75 Kreuzer M. Stamenković S.; Chen, S.; Andjus, P.; Dučić T. Lipids status and copper in a single astrocyte of the rat model for amyotrophic lateral sclerosis: Correlative synchrotron‐based X‐ray and infrared imaging. J. Biophotonics 2020 13 10 e202000069 10.1002/jbio.202000069 32463554
76 Abati E. Bresolin N. Comi G. Corti S. Silence superoxide dismutase 1 (SOD1): a promising therapeutic target for amyotrophic lateral sclerosis (ALS). Expert Opin. Ther. Targets 2020 24 4 295 310 10.1080/14728222.2020.1738390 32125907
77 Hilton J.B. White A.R. Crouch P.J. Metal-deficient SOD1 in amyotrophic lateral sclerosis. J. Mol. Med. (Berl.) 2015 93 5 481 487 10.1007/s00109-015-1273-3 25754173
78 Enge T.G. Ecroyd H. Jolley D.F. Yerbury J.J. Kalmar B. Dosseto A. Assessment of metal concentrations in the SOD1G93A mouse model of amyotrophic lateral sclerosis and its potential role in muscular denervation, with particular focus on muscle tissue. Mol. Cell. Neurosci. 2018 88 319 329 10.1016/j.mcn.2018.03.001 29524628
79 Tokuda E. Nomura T. Ohara S. Watanabe S. Yamanaka K. Morisaki Y. Misawa H. Furukawa Y. A copper-deficient form of mutant Cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis. Biochim. Biophys. Acta Mol. Basis Dis. 2018 1864 6 2119 2130 10.1016/j.bbadis.2018.03.015 29551730
80 Sirangelo I. Iannuzzi C. The role of metal binding in the amyotrophic lateral sclerosis-related aggregation of copper-zinc superoxide dismutase. Molecules 2017 22 9 1429 10.3390/molecules22091429 28850080
81 Sauzéat L. Bernard E. Perret-Liaudet A. Quadrio I. Vighetto A. Krolak-Salmon P. Broussolle E. Leblanc P. Balter V. Isotopic evidence for disrupted copper metabolism in amyotrophic lateral sclerosis. iScience 2018 6 264 271 10.1016/j.isci.2018.07.023 30240616
82 Tarnacka B. Jopowicz A. Maślińska, M. Copper, iron, and manganese toxicity in neuropsychiatric conditions. Int. J. Mol. Sci. 2021 22 15 7820 10.3390/ijms22157820 34360586
83 Kurlander H.M. Patten B.M. Metals in spinal cord tissue of patients dying of motor neuron disease. Ann. Neurol. 1979 6 1 21 24 10.1002/ana.410060105 507754
84 Katzeff J.S. Bright F. Phan K. Kril J.J. Ittner L.M. Kassiou M. Hodges J.R. Piguet O. Kiernan M.C. Halliday G.M. Kim W.S. Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis. Brain 2022 145 5 1598 1609 10.1093/brain/awac077 35202463
85 Tokuda E. Ono S. Ishige K. Watanabe S. Okawa E. Ito Y. Suzuki T. Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis. Exp. Neurol. 2008 213 1 122 128 10.1016/j.expneurol.2008.05.011 18617166
86 Bandmann O. Weiss K.H. Kaler S.G. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 2015 14 1 103 113 10.1016/S1474-4422(14)70190-5 25496901
87 Lalioti V. Sandoval I. Cassio D. Duclos-Vallée J.C. Molecular pathology of Wilson’s disease: A brief. J. Hepatol. 2010 53 6 1151 1153 10.1016/j.jhep.2010.07.008 20832891
88 Xu R. Jiang Y. Zhang Y. Yang X. The optimal threshold of serum ceruloplasmin in the diagnosis of Wilson’s disease: A large hospital-based study. PLoS One 2018 13 1 e0190887 10.1371/journal.pone.0190887 29324775
89 Yang Y. Hao W. Wei T. Tang L. Qian N. Yang Y. Xi H. Zhang S. Yang W. Role of serum ceruloplasmin in the diagnosis of Wilson’s disease: A large Chinese study. Front. Neurol. 2022 13 1058642 10.3389/fneur.2022.1058642 36570465
90 Ala A. Walker A.P. Ashkan K. Dooley J.S. Schilsky M.L. Wilson’s disease. Lancet 2007 369 9559 397 408 10.1016/S0140-6736(07)60196-2 17276780
91 Lutsenko S. Atp7b −/− mice as a model for studies of Wilson’s disease. Biochem. Soc. Trans. 2008 36 6 1233 1238 10.1042/BST0361233 19021531
92 Wooton-Kee C.R. Jain A.K. Wagner M. Grusak M.A. Finegold M.J. Lutsenko S. Moore D.D. Elevated copper impairs hepatic nuclear receptor function in Wilson’s disease. J. Clin. Invest. 2015 125 9 3449 3460 10.1172/JCI78991 26241054
93 Shribman S. Poujois A. Bandmann O. Czlonkowska A. Warner T.T. Wilson’s disease: update on pathogenesis, biomarkers and treatments. J. Neurol. Neurosurg. Psychiatry 2021 92 10 1053 1061 10.1136/jnnp-2021-326123 34341141
94 Zischka H. Lichtmannegger J. Pathological mitochondrial copper overload in livers of Wilson’s disease patients and related animal models. Ann. N. Y. Acad. Sci. 2014 1315 1 6 15 10.1111/nyas.12347 24517326
95 Litwin T. Gromadzka G. Szpak G.M. Jabłonka-Salach, K.; Bulska, E.; Członkowska, A. Brain metal accumulation in Wilson’s disease. J. Neurol. Sci. 2013 329 1-2 55 58 10.1016/j.jns.2013.03.021 23597670
96 Lech T. Hydzik P. Kosowski B. Significance of copper determination in late onset of Wilson’s disease. Clin. Toxicol. (Phila.) 2007 45 6 688 694 10.1080/15563650701502535 17849244
97 Sokol R.J. Twedt D. McKim J.M. Jr Devereaux M.W. Karrer F.M. Kam I. Von Steigman G. Narkewicz M.R. Bacon B.R. Britton R.S. Neuschwander-Tetri B.A. Oxidant injury to hepatic mitochondria in patients with Wilson’s disease and Bedlington terriers with copper toxicosis. Gastroenterology 1994 107 6 1788 1798 10.1016/0016-5085(94)90822-2 7958693
98 Brewer G.J. Askari F. Dick R.B. Sitterly J. Fink J.K. Carlson M. Kluin K.J. Lorincz M.T. Treatment of Wilson’s disease with tetrathiomolybdate: V. control of free copper by tetrathiomolybdate and a comparison with trientine. Transl. Res. 2009 154 2 70 77 10.1016/j.trsl.2009.05.002 19595438
99 Tümer Z. An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome. Hum. Mutat. 2013 34 3 417 429 10.1002/humu.22266 23281160
100 Donsante A. Yi L. Zerfas P.M. Brinster L.R. Sullivan P. Goldstein D.S. Prohaska J. Centeno J.A. Rushing E. Kaler S.G. ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model. Mol. Ther. 2011 19 12 2114 2123 10.1038/mt.2011.143 21878905
101 Bertini I. Rosato A. Menkes disease. Cell. Mol. Life Sci. 2008 65 1 89 91 10.1007/s00018-007-7439-6 17989919
102 Lenartowicz M. Krzeptowski W. Lipiński, P.; Grzmil, P.; Starzyński, R.; Pierzchała, O.; Møller, L.B. Mottled mice and non-mammalian models of Menkes disease. Front. Mol. Neurosci. 2015 8 72 10.3389/fnmol.2015.00072 26732058
103 Giampietro R. Spinelli F. Contino M. Colabufo N.A. The pivotal role of copper in neurodegeneration: A new strategy for the therapy of neurodegenerative disorders. Mol. Pharm. 2018 15 3 808 820 10.1021/acs.molpharmaceut.7b00841 29323501
104 Horn N. Wittung-Stafshede P. ATP7A-regulated enzyme metalation and trafficking in the Menkes disease puzzle. Biomedicines 2021 9 4 391 10.3390/biomedicines9040391 33917579
105 Guo Y. Xia W. Peng X. Shao J. Almost misdiagnosed Menkes disease: A case report. Heliyon 2022 8 4 e09268 10.1016/j.heliyon.2022.e09268 35464712
106 Aguzzi A. Zhu C. Microglia in prion diseases. J. Clin. Invest. 2017 127 9 3230 3239 10.1172/JCI90605 28714865
107 Choi C.J. Kanthasamy A. Anantharam V. Kanthasamy A.G. Interaction of metals with prion protein: Possible role of divalent cations in the pathogenesis of prion diseases. Neurotoxicology 2006 27 5 777 787 10.1016/j.neuro.2006.06.004 16860868
108 Johnson R.T. Prion diseases. Lancet Neurol. 2005 4 10 635 642 10.1016/S1474-4422(05)70192-7 16168932
109 Unterberger U. Voigtländer T. Budka H. Pathogenesis of prion diseases. Acta Neuropathol. 2005 109 1 32 48 10.1007/s00401-004-0953-9 15645262
110 Kawahara M. Kato-Negishi M. Tanaka K. Neurometals in the pathogenesis of Prion diseases. Int. J. Mol. Sci. 2021 22 3 1267 10.3390/ijms22031267 33525334
111 Kretzschmar H.A. Molecular pathogenesis of prion diseases. Eur. Arch. Psychiatry Clin. Neurosci. 1999 249 S3 Suppl. 3 S56 S63 10.1007/PL00014175 10654101
112 Aguzzi A. Nuvolone M. Zhu C. The immunobiology of prion diseases. Nat. Rev. Immunol. 2013 13 12 888 902 10.1038/nri3553 24189576
113 Soto C. Satani N. The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol. Med. 2011 17 1 14 24 10.1016/j.molmed.2010.09.001 20889378
114 Aguzzi A. Heikenwalder M. Pathogenesis of prion diseases: current status and future outlook. Nat. Rev. Microbiol. 2006 4 10 765 775 10.1038/nrmicro1492 16980938
115 Wong B.S. Chen S.G. Colucci M. Xie Z. Pan T. Liu T. Li R. Gambetti P. Sy M.S. Brown D.R. Aberrant metal binding by prion protein in human prion disease. J. Neurochem. 2001 78 6 1400 1408 10.1046/j.1471-4159.2001.00522.x 11579148
116 Leach S.P. Salman M.D. Hamar D. Trace elements and prion diseases: a review of the interactions of copper, manganese and zinc with the prion protein. Anim. Health Res. Rev. 2006 7 1-2 97 105 10.1017/S1466252307001181 17389057
117 Meneghetti E. Gasperini L. Virgilio T. Moda F. Tagliavini F. Benetti F. Legname G. Prions strongly reduce NMDA receptor s-nitrosylation levels at pre-symptomatic and terminal stages of Prion diseases. Mol. Neurobiol. 2019 56 9 6035 6045 10.1007/s12035-019-1505-6 30710214
118 Emwas A.H.M. Al-Talla Z.A. Guo X. Al-Ghamdi S. Al-Masri H.T. Utilizing NMR and EPR spectroscopy to probe the role of copper in prion diseases. Magn. Reson. Chem. 2013 51 5 255 268 10.1002/mrc.3936 23436479
119 Varela-Nallar L. González A. Inestrosa N. Role of copper in prion diseases: deleterious or beneficial? Curr. Pharm. Des. 2006 12 20 2587 2595 10.2174/138161206777698873 16842180
120 Lehmann S. Metal ions and prion diseases. Curr. Opin. Chem. Biol. 2002 6 2 187 192 10.1016/S1367-5931(02)00295-8 12039003
121 Alsiary R.A. Alghrably M. Saoudi A. Al-Ghamdi S. Jaremko L. Jaremko M. Emwas A.H. Using NMR spectroscopy to investigate the role played by copper in prion diseases. Neurol. Sci. 2020 41 9 2389 2406 10.1007/s10072-020-04321-9 32328835
122 Bounias M. Purdey M. Transmissible spongiform encephalopathies: a family of etiologically complex diseases—a review. Sci. Total Environ. 2002 297 1-3 1 19 10.1016/S0048-9697(02)00140-7 12389776
123 Bar-Or A. Li R. Cellular immunology of relapsing multiple sclerosis: interactions, checks, and balances. Lancet Neurol. 2021 20 6 470 483 10.1016/S1474-4422(21)00063-6 33930317
124 Bierhansl L. Hartung H.P. Aktas O. Ruck T. Roden M. Meuth S.G. Thinking outside the box: non-canonical targets in multiple sclerosis. Nat. Rev. Drug Discov. 2022 21 8 578 600 10.1038/s41573-022-00477-5 35668103
125 Colombo E. Triolo D. Bassani C. Bedogni F. Di Dario M. Dina G. Fredrickx E. Fermo I. Martinelli V. Newcombe J. Taveggia C. Quattrini A. Comi G. Farina C. Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes. Proc. Natl. Acad. Sci. USA 2021 118 27 e2025804118 10.1073/pnas.2025804118 34183414
126 Malosio M.L. Tecchio F. Squitti R. Molecular mechanisms underlying copper function and toxicity in neurons and their possible therapeutic exploitation for Alzheimer’s disease. Aging Clin. Exp. Res. 2021 33 7 2027 2030 10.1007/s40520-019-01463-5 31965480
127 Burk K. Pasterkamp R.J. Disrupted neuronal trafficking in amyotrophic lateral sclerosis. Acta Neuropathol. 2019 137 6 859 877 10.1007/s00401-019-01964-7 30721407
128 Fasae K.D. Abolaji A.O. Faloye T.R. Odunsi A.Y. Oyetayo B.O. Enya J.I. Rotimi J.A. Akinyemi R.O. Whitworth A.J. Aschner M. Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: Limitations, and current and future perspectives. J. Trace Elem. Med. Biol. 2021 67 126779 10.1016/j.jtemb.2021.126779 34034029
129 Barnham K.J. Bush A.I. Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem. Soc. Rev. 2014 43 19 6727 6749 10.1039/C4CS00138A 25099276
130 Das N. Raymick J. Sarkar S. Role of metals in Alzheimer’s disease. Metab. Brain Dis. 2021 36 7 1627 1639 10.1007/s11011-021-00765-w 34313926
131 Davies K.M. Mercer J.F.B. Chen N. Double K.L. Copper dyshomoeostasis in Parkinson’s disease: implications for pathogenesis and indications for novel therapeutics. Clin. Sci. (Lond.) 2016 130 8 565 574 10.1042/CS20150153 26957644
132 Safety, tolerability, and efficacy of PBT2 in Huntington’s disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015 14 1 39 47 10.1016/S1474-4422(14)70262-5 25467848
133 Choi B.Y. Jang B.G. Kim J.H. Seo J.N. Wu G. Sohn M. Chung T.N. Suh S.W. Copper/zinc chelation by clioquinol reduces spinal cord white matter damage and behavioral deficits in a murine MOG-induced multiple sclerosis model. Neurobiol. Dis. 2013 54 382 391 10.1016/j.nbd.2013.01.012 23360710
134 Hung Y.H. Bush A.I. Cherny R.A. Copper in the brain and Alzheimer’s disease. J. Biol. Inorg. Chem. 2010 15 1 61 76 10.1007/s00775-009-0600-y 19862561
135 Squitti R. Rossini P.M. Cassetta E. Moffa F. Pasqualetti P. Cortesi M. Colloca A. Rossi L. Finazzi-Agró A. d-penicillamine reduces serum oxidative stress in Alzheimer’s disease patients. Eur. J. Clin. Invest. 2002 32 1 51 59 10.1046/j.1365-2362.2002.00933.x 11851727
136 Brewer G.J. Askari F.K. Wilson's disease: Clinical management and therapy. J Hepatol. 2005 42 Suppl(1) S13 S21 10.1016/j.jhep.2004.11.013 15777568
137 Nomura S. Nozaki S. Hamazaki T. Takeda T. Ninomiya E. Kudo S. Hayashinaka E. Wada Y. Hiroki T. Fujisawa C. Kodama H. Shintaku H. Watanabe Y. PET imaging analysis with 64Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model. J. Nucl. Med. 2014 55 5 845 851 10.2967/jnumed.113.131797 24627433
138 Zhao J. Shi Q. Tian H. Li Y. Liu Y. Xu Z. Robert A. Liu Q. Meunier B. TDMQ20, a specific copper chelator, reduces memory impairments in Alzheimer’s disease mouse models. ACS Chem. Neurosci. 2021 12 1 140 149 10.1021/acschemneuro.0c00621 33322892
139 Tümer Z. Møller L.B. Menkes disease. Eur. J. Hum. Genet. 2010 18 5 511 518 10.1038/ejhg.2009.187 19888294
140 Squitti R. Siotto M. Arciello M. Rossi L. Non-ceruloplasmin bound copper and ATP7B gene variants in Alzheimer’s disease. Metallomics 2016 8 9 863 873 10.1039/C6MT00101G 27499330
141 Lalioti V. Tsubota A. Sandoval I. Disorders in hepatic copper secretion: Wilson’s disease and pleomorphic syndromes. Semin. Liver Dis. 2017 37 2 175 188 10.1055/s-0037-1602764 28564725
142 Mathys Z.K. White A.R. Copper and Alzheimer’s disease. Adv. Neurobiol. 2017 18 199 216 10.1007/978-3-319-60189-2_10 28889269
143 Ellett L.J. Hung L.W. Munckton R. Sherratt N.A. Culvenor J. Grubman A. Furness J.B. White A.R. Finkelstein D.I. Barnham K.J. Lawson V.A. Restoration of intestinal function in an MPTP model of Parkinson’s Disease. Sci. Rep. 2016 6 1 30269 10.1038/srep30269 27471168
144 Abbaoui A. Chatoui H. El Hiba O. Gamrani H. Neuroprotective effect of curcumin-I in copper-induced dopaminergic neurotoxicity in rats: A possible link with Parkinson’s disease. Neurosci. Lett. 2017 660 103 108 10.1016/j.neulet.2017.09.032 28919537
145 Roberts B.R. Lim N.K.H. McAllum E.J. Donnelly P.S. Hare D.J. Doble P.A. Turner B.J. Price K.A. Chun Lim S. Paterson B.M. Hickey J.L. Rhoads T.W. Williams J.R. Kanninen K.M. Hung L.W. Liddell J.R. Grubman A. Monty J.F. Llanos R.M. Kramer D.R. Mercer J.F.B. Bush A.I. Masters C.L. Duce J.A. Li Q.X. Beckman J.S. Barnham K.J. White A.R. Crouch P.J. Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis. J. Neurosci. 2014 34 23 8021 8031 10.1523/JNEUROSCI.4196-13.2014 24899723
146 Tokuda E. Furukawa Y. Copper homeostasis as a therapeutic target in amyotrophic lateral sclerosis with sod1 mutations. Int. J. Mol. Sci. 2016 17 5 636 10.3390/ijms17050636 27136532
147 Guthrie L.M. Soma S. Yuan S. Silva A. Zulkifli M. Snavely T.C. Greene H.F. Nunez E. Lynch B. De Ville C. Shanbhag V. Lopez F.R. Acharya A. Petris M.J. Kim B.E. Gohil V.M. Sacchettini J.C. Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice. Science 2020 368 6491 620 625 10.1126/science.aaz8899 32381719
148 Kempuraj D. Thangavel R. Kempuraj D.D. Ahmed M.E. Selvakumar G.P. Raikwar S.P. Zaheer S.A. Iyer S.S. Govindarajan R. Chandrasekaran P.N. Zaheer A. Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma. Biofactors 2021 47 2 190 197 10.1002/biof.1687 33098588
149 Liu Q.S. Jiang H.L. Wang Y. Wang L.L. Zhang J.X. He C.H. Shao S. Zhang T.T. Xing J.G. Liu R. Total flavonoid extract from Dracoephalum moldavica L. attenuates β-amyloid-induced toxicity through anti-amyloidogenesic and neurotrophic pathways. Life Sci. 2018 193 214 225 10.1016/j.lfs.2017.10.041 29100755
150 Liu R. Meng F. Zhang L. Liu A. Qin H. Lan X. Li L. Du G. Luteolin isolated from the medicinal plant Elsholtzia rugulosa (Labiatae) prevents copper-mediated toxicity in β-amyloid precursor protein Swedish mutation overexpressing SH-SY5Y cells. Molecules 2011 16 3 2084 2096 10.3390/molecules16032084 21368720
151 Xu Y. Yang J. Lu Y. Qian L.L. Yang Z.Y. Han R.M. Zhang J.P. Skibsted L.H. Copper(II) coordination and translocation in luteolin and effect on radical scavenging. J. Phys. Chem. B 2020 124 2 380 388 10.1021/acs.jpcb.9b10531 31845805
152 Zhao L. Wang J.L. Liu R. Li X.X. Li J.F. Zhang L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model. Molecules 2013 18 8 9949 9965 10.3390/molecules18089949 23966081
153 Zhao L. Wang J. Wang Y. Fa X. Apigenin attenuates copper-mediated β-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model. Brain Res. 2013 1492 33 45 10.1016/j.brainres.2012.11.019 23178511
154 Peng H. Xing Y. Gao L. Zhang L. Zhang G. Simultaneous separation of apigenin, luteolin and rosmarinic acid from the aerial parts of the copper-tolerant plant Elsholtzia splendens. Environ. Sci. Pollut. Res. Int. 2014 21 13 8124 8132 10.1007/s11356-014-2747-5 24671394
155 Wang Q. Jiang H. Wang L. Yi H. Li Z. Liu R. Vitegnoside mitigates neuronal injury, mitochondrial apoptosis, and inflammation in an Alzheimer’s disease cell model via the p38 MAPK/JNK Pathway. J. Alzheimers Dis. 2019 72 1 199 214 10.3233/JAD-190640 31561371
156 Lin M.C. Liu C.C. Liao C.S. Ro J.H. Neuroprotective effect of quercetin during cerebral ischemic injury involves regulation of essential elements, transition metals, cu/zn ratio, and antioxidant activity. Molecules 2021 26 20 6128 10.3390/molecules26206128 34684707
157 Yang D. Wang T. Long M. Li P. Quercetin: its main pharmacological activity and potential application in clinical medicine. Oxid. Med. Cell. Longev. 2020 2020 1 13 10.1155/2020/8825387 33488935
158 Du G. Zhao Z. Chen Y. Li Z. Tian Y. Liu Z. Liu B. Song J. Quercetin protects rat cortical neurons against traumatic brain injury. Mol. Med. Rep. 2018 17 6 7859 7865 10.3892/mmr.2018.8801 29620218
159 Jomova K. Lawson M. Drostinova L. Lauro P. Poprac P. Brezova V. Michalik M. Lukes V. Valko M. Protective role of quercetin against copper(II)-induced oxidative stress: A spectroscopic, theoretical and DNA damage study. Food Chem. Toxicol. 2017 110 340 350 10.1016/j.fct.2017.10.042 29107026
160 Chakraborty J. Pakrashi S. Sarbajna A. Dutta M. Bandyopadhyay J. Quercetin attenuates copper-induced apoptotic cell death and endoplasmic reticulum stress in SH-SY5Y cells by autophagic modulation. Biol. Trace Elem. Res. 2022 200 12 5022 5041 10.1007/s12011-022-03093-x 35149956
161 Zubčić K.; Radovanović V.; Vlainić J.; Hof, P.R.; Oršolić N.; Šimić G.; Jazvinšćak Jembrek, M. PI3K/Akt and ERK1/2 signalling are involved in quercetin-mediated neuroprotection against copper-induced injury. Oxid. Med. Cell. Longev. 2020 2020 1 14 10.1155/2020/9834742 32733640
162 Kuo S.M. Huang C.T. Blum P. Chang C. Quercetin cumulatively enhances copper induction of metallothionein in intestinal cells. Biol. Trace Elem. Res. 2001 84 1-3 001 010 10.1385/BTER:84:1-3:001 11817679
163 Gan R.Y. Li H.B. Sui Z.Q. Corke H. Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): An updated review. Crit. Rev. Food Sci. Nutr. 2018 58 6 924 941 10.1080/10408398.2016.1231168 27645804
164 Steinmann J. Buer J. Pietschmann T. Steinmann E. Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea. Br. J. Pharmacol. 2013 168 5 1059 1073 10.1111/bph.12009 23072320
165 Koh S.H. Lee S.M. Kim H.Y. Lee K.Y. Lee Y.J. Kim H.T. Kim J. Kim M.H. Hwang M.S. Song C. Yang K.W. Lee K.W. Kim S.H. Kim O.H. The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice. Neurosci. Lett. 2006 395 2 103 107 10.1016/j.neulet.2005.10.056 16356650
166 Teng Y. Zhao J. Ding L. Ding Y. Zhou P. Complex of EGCG with Cu(II) suppresses amyloid aggregation and Cu(II)-induced cytotoxicity of alpha-synuclein. Molecules 2019 24 16 2940 10.3390/molecules24162940 31416122
167 Li J. Xiang H. Huang C. Lu J. Pharmacological actions of myricetin in the nervous system: a comprehensive review of preclinical studies in animals and cell models. Front. Pharmacol. 2021 12 797298 10.3389/fphar.2021.797298 34975495
168 Zhang X.H. Ma Z.G. Rowlands D.K. Gou Y.L. Fok K.L. Wong H.Y. Yu M.K. Tsang L.L. Mu L. Chen L. Yung W.H. Chung Y.W. Zhang B.L. Zhao H. Chan H.C. Flavonoid myricetin modulates GABA(A) receptor activity through activation of Ca(2+) channels and CaMK-II pathway. Evid. Based Complement. Alternat. Med. 2012 2012 1 10 10.1155/2012/758097 23258999
169 Ding P. Liao X. Shi B. Adsorption chromatography separation of the flavonols kaempferol, quercetin and myricetin using cross-linked collagen fibre as the stationary phase. J. Sci. Food Agric. 2013 93 7 1575 1583 10.1002/jsfa.5924 23152137
170 DeToma A.S. Choi J.S. Braymer J.J. Lim M.H. Myricetin: a naturally occurring regulator of metal-induced amyloid-β aggregation and neurotoxicity. ChemBioChem 2011 12 8 1198 1201 10.1002/cbic.201000790 21538759
171 Xiang B. Li D. Chen Y. Li M. Zhang Y. Sun T. Tang S. Curcumin ameliorates copper-induced neurotoxicity through inhibiting oxidative stress and mitochondrial apoptosis in SH-SY5Y cells. Neurochem. Res. 2021 46 2 367 378 10.1007/s11064-020-03173-1 33201401
172 Abolaji A.O. Fasae K.D. Iwezor C.E. Aschner M. Farombi E.O. Curcumin attenuates copper-induced oxidative stress and neurotoxicity in Drosophila melanogaster. Toxicol. Rep. 2020 7 261 268 10.1016/j.toxrep.2020.01.015 32025502
173 RA Mans D. Djotaroeno, M.; Friperson, P.; Pawirodihardjo, J. Phytochemical and pharmacological support for the traditional uses of Zingiberacea species in suriname - a review of the literature. Pharmacogn. J. 2019 11 6s 1511 1525 10.5530/pj.2019.11.232
174 Abbaoui A. Gamrani H. Obvious anxiogenic-like effects of subchronic copper intoxication in rats, outcomes on spatial learning and memory and neuromodulatory potential of curcumin. J. Chem. Neuroanat. 2019 96 86 93 10.1016/j.jchemneu.2019.01.001 30611899
175 Ho W.I. Hu Y. Cheng C.W. Wei R. Yang J. Li N. Au K.W. Tse Y.L. Wang Q. Ng K.M. Esteban M.A. Tse H.F. Liposome-encapsulated curcumin attenuates HMGB1-mediated hepatic inflammation and fibrosis in a murine model of Wilson’s disease. Biomed. Pharmacother. 2022 152 113197 10.1016/j.biopha.2022.113197 35687913
176 Motavaf M. Sadeghizadeh M. Babashah S. Zare L. Javan M. Protective effects of a nano-formulation of curcumin against cuprizone-induced demyelination in the mouse corpus callosum. Iran. J. Pharm. Res. 2020 19 3 310 320 33680032
177 Huang H.C. Lin C.J. Liu W.J. Jiang R.R. Jiang Z.F. Dual effects of curcumin on neuronal oxidative stress in the presence of Cu(II). Food Chem. Toxicol. 2011 49 7 1578 1583 10.1016/j.fct.2011.04.004 21501647
178 Sarawi W.S. Alhusaini A.M. Fadda L.M. Alomar H.A. Albaker A.B. Aljrboa A.S. Alotaibi A.M. Hasan I.H. Mahmoud A.M. Curcumin and Nano-curcumin mitigate copper neurotoxicity by modulating oxidative stress, inflammation, and Akt/GSK-3beta signaling. Molecules 2021 26 18 5591 10.3390/molecules26185591 34577062
179 Abbaoui A. Gamrani H. Neuronal, astroglial and locomotor injuries in subchronic copper intoxicated rats are repaired by curcumin: A possible link with Parkinson’s disease. Acta Histochem. 2018 120 6 542 550 10.1016/j.acthis.2018.06.005 29954586
180 Lin R. Chen X. Li W. Han Y. Liu P. Pi R. Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: Blockage by curcumin. Neurosci. Lett. 2008 440 3 344 347 10.1016/j.neulet.2008.05.070 18583042
181 Enogieru A.B. Haylett W. Hiss D.C. Bardien S. Ekpo O.E. Rutin as a Potent antioxidant: implications for neurodegenerative disorders. Oxid. Med. Cell. Longev. 2018 2018 1 17 10.1155/2018/6241017 30050657
182 Arowoogun J. Akanni O.O. Adefisan A.O. Owumi S.E. Tijani A.S. Adaramoye O.A. Rutin ameliorates copper sulfate‐induced brain damage via antioxidative and anti‐inflammatory activities in rats. J. Biochem. Mol. Toxicol. 2021 35 1 e22623 10.1002/jbt.22623 32881150
183 Lin M.C. Liu C.C. Lin Y.C. Liao C.S. Resveratrol protects against cerebral ischemic injury via restraining lipid peroxidation, transition elements, and toxic metal levels, but enhancing anti-oxidant activity. Antioxidants 2021 10 10 1515 10.3390/antiox10101515 34679650
184 Tian C. Zhang R. Ye X. Zhang C. Jin X. Yamori Y. Hao L. Sun X. Ying C. Resveratrol ameliorates high-glucose-induced hyperpermeability mediated by caveolae via VEGF/KDR pathway. Genes Nutr. 2013 8 2 231 239 10.1007/s12263-012-0319-1 22983702
185 Majewski M. Ognik K. Thoene M. Rawicka A. Juśkiewicz, J. Resveratrol modulates the blood plasma levels of Cu and Zn, the antioxidant status and the vascular response of thoracic arteries in copper deficient Wistar rats. Toxicol. Appl. Pharmacol. 2020 390 114877 10.1016/j.taap.2020.114877 31917326
186 Matos L. Gouveia A.M. Almeida H. Resveratrol attenuates copper-induced senescence by improving cellular proteostasis. Oxid. Med. Cell. Longev. 2017 2017 3793817 28280523
187 Asadi S. Moradi M.N. Khyripour N. Goodarzi M.T. Mahmoodi M. Resveratrol attenuates copper and zinc homeostasis and ameliorates oxidative stress in Type 2 diabetic rats. Biol. Trace Elem. Res. 2017 177 1 132 138 10.1007/s12011-016-0861-6 27744600
188 Muselin F. Gârban Z. Cristina R.T. Doma A.O. Dumitrescu E. Vițălaru, A.B.; Bănățean-Dunea, I. Homeostatic changes of some trace elements in geriatric rats in the condition of oxidative stress induced by aluminum and the beneficial role of resveratrol. J. Trace Elem. Med. Biol. 2019 55 136 142 10.1016/j.jtemb.2019.06.013 31345351
189 Majewski M. Ognik K. Juśkiewicz, J. The interaction between resveratrol and two forms of copper as carbonate and nanoparticles on antioxidant mechanisms and vascular function in Wistar rats. Pharmacol. Rep. 2019 71 5 862 869 10.1016/j.pharep.2019.03.011 31408785
190 Khalid S. Afzal N. Khan J.A. Hussain Z. Qureshi A.S. Anwar H. Jamil Y. Antioxidant resveratrol protects against copper oxide nanoparticle toxicity in vivo. Naunyn Schmiedebergs Arch. Pharmacol. 2018 391 10 1053 1062 10.1007/s00210-018-1526-0 29936585
191 Summers K.L. Roseman G.P. Sopasis G.J. Millhauser G.L. Harris H.H. Pickering I.J. George G.N. Copper(II) binding to pbt2 differs from that of other 8-hydroxyquinoline chelators: implications for the treatment of neurodegenerative protein misfolding diseases. Inorg. Chem. 2020 59 23 17519 17534 10.1021/acs.inorgchem.0c02754 33226796
192 Dzieżyc, K.; Karliński, M.; Litwin, T.; Członkowska, A. Compliant treatment with anti-copper agents prevents clinically overt Wilson’s disease in pre-symptomatic patients. Eur. J. Neurol. 2014 21 2 332 337 10.1111/ene.12320 24313946
193 Kaler S.G. Holmes C.S. Goldstein D.S. Tang J. Godwin S.C. Donsante A. Liew C.J. Sato S. Patronas N. Neonatal diagnosis and treatment of Menkes disease. N. Engl. J. Med. 2008 358 6 605 614 10.1056/NEJMoa070613 18256395
194 Tosato M. Di Marco V. Metal chelation therapy and Parkinson’s disease: a critical review on the thermodynamics of complex formation between relevant metal ions and promising or established drugs. Biomolecules 2019 9 7 269 10.3390/biom9070269 31324037
195 Gou D.H. Huang T.T. Li W. Gao X.D. Haikal C. Wang X.H. Song D.Y. Liang X. Zhu L. Tang Y. Ding C. Li J.Y. Inhibition of copper transporter 1 prevents α-synuclein pathology and alleviates nigrostriatal degeneration in AAV-based mouse model of Parkinson’s disease. Redox Biol. 2021 38 101795 10.1016/j.redox.2020.101795 33232911
196 Chen L. Min J. Wang F. Copper homeostasis and cuproptosis in health and disease. Signal Transduct. Target. Ther. 2022 7 1 378 10.1038/s41392-022-01229-y 36414625
197 Arnal N. Morel G.R. de Alaniz M.J.T. Castillo O. Marra C.A. Role of copper and cholesterol association in the neurodegenerative process. Int. J. Alzheimers Dis. 2013 2013 1 15 10.1155/2013/414817 24288650
198 Murillo O. Collantes M. Gazquez C. Moreno D. Hernandez-Alcoceba R. Barberia M. Ecay M. Tamarit B. Douar A. Ferrer V. Combal J.P. Peñuelas I. Bénichou B. Gonzalez-Aseguinolaza G. High value of 64Cu as a tool to evaluate the restoration of physiological copper excretion after gene therapy in Wilson’s disease. Mol. Ther. Methods Clin. Dev. 2022 26 98 106 10.1016/j.omtm.2022.06.001 35795774
199 Cai H. Cheng X. Wang X.P. ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson’s disease. Hepatology 2022 76 4 1046 1057 10.1002/hep.32484 35340061
200 Du A. Cai R. Shi J. Wu Q. Protective effects of icariin on traumatic brain injury. Curr. Neurovasc. Res. 2021 18 5 508 514 10.2174/1567202619666211223125628 34951380
201 Abbaoui A. Hiba O.E. Gamrani H. Neuroprotective potential of Aloe arborescens against copper induced neurobehavioral features of Parkinson’s disease in rat. Acta Histochem. 2017 119 5 592 601 10.1016/j.acthis.2017.06.003 28619286
202 Pan C. Liu N. Zhang P. Wu Q. Deng H. Xu F. Lian L. Liang Q. Hu Y. Zhu S. Tang Z. EGb761 ameliorates neuronal apoptosis and promotes angiogenesis in experimental intracerebral hemorrhage via RSK1/GSK3beta pathway. Mol. Neurobiol. 2018 55 2 1556 1567 10.1007/s12035-016-0363-8 28185127
203 Rojas P. Montes S. Serrano-García N. Rojas-Castañeda J. Effect of EGb761 supplementation on the content of copper in mouse brain in an animal model of Parkinson’s disease. Nutrition 2009 25 4 482 485 10.1016/j.nut.2008.10.013 19091511
204 Cao J. Li C. Ma P. Ding Y. Gao J. Jia Q. Zhu J. Zhang T. Effect of kaempferol on IgE-mediated anaphylaxis in C57BL/6 mice and LAD2 cells. Phytomedicine 2020 79 153346 10.1016/j.phymed.2020.153346 33002828
205 Simunkova M. Barbierikova Z. Jomova K. Hudecova L. Lauro P. Alwasel S.H. Alhazza I. Rhodes C.J. Valko M. Antioxidant vs. Prooxidant properties of the flavonoid, kaempferol, in the presence of Cu(II) ions: a ros-scavenging activity, fenton reaction and dna damage study. Int. J. Mol. Sci. 2021 22 4 1619 10.3390/ijms22041619 33562744
206 Fachel F.N.S. Schuh R.S. Veras K.S. Bassani V.L. Koester L.S. Henriques A.T. Braganhol E. Teixeira H.F. An overview of the neuroprotective potential of rosmarinic acid and its association with nanotechnology-based delivery systems: A novel approach to treating neurodegenerative disorders. Neurochem. Int. 2019 122 47 58 10.1016/j.neuint.2018.11.003 30439384
207 Kola A. Hecel A. Lamponi S. Valensin D. Novel perspective on Alzheimer’s disease treatment: rosmarinic acid molecular interplay with Copper(II) and amyloid beta. Life (Basel) 2020 10 7 118 10.3390/life10070118 32698429
208 Costa I.M. Lima F.O.V. Fernandes L.C.B. Norrara B. Neta F.I. Alves R.D. Cavalcanti J.R.L.P. Lucena E.E.S. Cavalcante J.S. Rego A.C.M. Filho I.A. Queiroz D.B. Freire M.A.M. Guzen F.P. Astragaloside IV supplementation promotes a neuroprotective effect in experimental models of neurological disorders: a systematic review. Curr. Neuropharmacol. 2019 17 7 648 665 10.2174/1570159X16666180911123341 30207235
209 Ma M. Qiu B. Jin J. Wang J. Nie Y. Liang Y. Yu Z. Teng C.B. Establishment of a specific in vivo Cu(Ⅰ) reporting system based on metallothionein screening. Metallomics 2021 13 7 mfab035 10.1093/mtomcs/mfab035 34114637
210 Memariani Z. Abbas S.Q. ul Hassan, S.S.; Ahmadi, A.; Chabra, A. Naringin and naringenin as anticancer agents and adjuvants in cancer combination therapy: Efficacy and molecular mechanisms of action, a comprehensive narrative review. Pharmacol. Res. 2021 171 105264 10.1016/j.phrs.2020.105264 33166734
211 Yuan J. Wei F. Luo X. Zhang M. Qiao R. Zhong M. Chen H. Yang W. Multi-component comparative pharmacokinetics in rats after oral administration of Fructus aurantii extract, naringin, neohesperidin, and naringin-neohesperidin. Front. Pharmacol. 2020 11 933 10.3389/fphar.2020.00933 32636752
212 Chen K.Y. Lin K.C. Chen Y.S. Yao C.H. A novel porous gelatin composite containing naringin for bone repair. Evid. Based Complement. Alternat. Med. 2013 2013 1 10 10.1155/2013/283941 23431335
213 Guo L.X. Sun, B. N′-1,10-Bis(Naringin) Triethylenetetraamine, synthesis and as a Cu(II) chelator for Alzheimer’s disease therapy. Biol. Pharm. Bull. 2021 44 1 51 56 10.1248/bpb.b20-00574 33162492
214 Saini R.K. Shuaib S. Goyal D. Goyal B. Insights into the inhibitory mechanism of a resveratrol and clioquinol hybrid against Aβ42 aggregation and protofibril destabilization: A molecular dynamics simulation study. J. Biomol. Struct. Dyn. 2019 37 12 3183 3197 10.1080/07391102.2018.1511475 30582723
215 Mao F. Yan J. Li J. Jia X. Miao H. Sun Y. Huang L. Li X. New multi-target-directed small molecules against Alzheimer’s disease: a combination of resveratrol and clioquinol. Org. Biomol. Chem. 2014 12 31 5936 5944 10.1039/C4OB00998C 24986600
