Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau

Squitti, Rosanna; Barbati, Giulia; Rossi, Luisa; Ventriglia, Mariacarla; Forno, Gloria Dal; Cesaretti, S.; Moffa, Filomena; Caridi, I.; Cassetta, Emanuele; Pasqualetti, Patrizio; Calabrese, Lilia; Lupoi, Domenico; Rossini, Paolo Maria

doi:10.1212/01.wnl.0000223343.82809.cf

Cited by 173 publications

(146 citation statements)

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“…25 A hint towards this interpretation comes from our estimation-via a clearance measure-that about 3% of serum 'free' copper crosses the BBB in living patients and possibly interact with Aβ. 15 The latter finding was recently confirmed by other authors, who demonstrated an interaction between copper and Aβ in the CSF, 26 probably resulting in catalytic generation of peroxides (H 2 O 2 ) and Aβ aggregation, 15,26 ultimately leading to neurodegeneration. 27 Alternative hypotheses could be put forward to explain ceruloplasmin fragmentation in AD.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 68%

“…There is new evidence suggesting that brain copper may redistribute outside the neuronal cell, leaving it relatively deficient. 7 Although past studies in man have found no differences between AD and controls in serum copper levels, [8][9][10][11] more sophisticated measurements have recently shown both an increase, [12][13][14][15] and a decrease of these levels, 16,17 thus opening a debate on a toxic or protective role of copper in AD. Results from our laboratory, though, suggest that it is the ceruloplasmin-copper relationship, rather than the level of absolute (i.e., bound and not bound to ceruloplasmin) serum copper, that may be the key issue in interpreting in vivo copper findings in AD.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, one must remember that 'free' copper represents the most important diagnostic marker for Wilson's disease-the paradigmatic disease of copper toxicosis and accumulation. 5,6 In particular, our recent biochemical studies demonstrated that a discrete concentration increase of copper occurs in AD which exceeds the amount of ceruloplasmin, 15 and that a considerable amount of inactive ceruloplasmin can be detected in the cerebrospinal fluid of AD patients. 20 Since ceruloplasmin is the main copper transporter in general circulation, we aimed in the present work at studying the qualitative changes occurring in the ceruloplasmin present in the serum of AD patients, explored by means of a two dimensional polyacrylamide gel electrophoresis (2-D PAGE) approach, to detect possible protein modifications that can be considered explanatory of 'free' copper deregulation.…”

Section: Introductionmentioning

confidence: 99%

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Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

Squitti

Quattrocchi

Salustri³

et al. 2008

Prion

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A dysfunction in copper homeostasis seems to occur in Alzheimer's disease (AD). We recently demonstrated that an excess of non-ceruloplasmin-copper (i.e., 'free' copper) correlates with the main functional and anatomical deficits as well as the cerebrospinal markers of the disease, thus suggesting that copper contributes to AD neurodegeneration. Aim of this study was to investigate the profile of serum ceruloplasmin isoforms immunoreactive protein in relation to copper dysfunction in AD. Twenty-five AD patients and 25 controls were included in the study. All subjects underwent individual measurements of serum ceruloplasmin and copper concentrations, and the amount of 'free' copper was computed for each copper and ceruloplasmin pair. Serum samples were also pooled and analyzed by two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and western blot analysis. The mean concentration of 'free' copper resulted higher in AD patients than in controls. Ceruloplasmin 2-D PAGE western blot analysis of pooled sera showed in the AD samples low-molecular-weight spots in the <50 kDa range that were not detected in controls' pooled sera (p < 0.029).Our data indicate a ceruloplasmin fragmentation in the serum of AD patients, possibly related to 'free' copper deregulation in this disease.

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Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

Squitti

Quattrocchi

Salustri³

et al. 2008

Prion

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“…2,3 A derangement of copper homeostasis leading to a labile pool may influence disease onset or progression. 4,5 This notion was initially claimed in several of our studies on the basis of evidence that a specific serum pool of copper, not bound to ceruloplasmin (also named ''free'' copper) was associated with some typical clinical signs and cerebrospinal fluid (CSF) markers of AD. 4,6 Recently some investigators 7 have strongly supported this notionby providing hard data demonstrating elevated levels of exchangeable Cu 2 + in samples of the AD brain correlating with tissue oxidative damage.…”

mentioning

confidence: 89%

“…4,5 This notion was initially claimed in several of our studies on the basis of evidence that a specific serum pool of copper, not bound to ceruloplasmin (also named ''free'' copper) was associated with some typical clinical signs and cerebrospinal fluid (CSF) markers of AD. 4,6 Recently some investigators 7 have strongly supported this notionby providing hard data demonstrating elevated levels of exchangeable Cu 2 + in samples of the AD brain correlating with tissue oxidative damage. 7,8 Labile copper, already reported as a marker of Wilson disease (WD) 9,10 -the paradigmatic disease of free copper toxicosis or intoxication-also has the potential to be a ''modifying'' or risk factor for AD.…”

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confidence: 89%

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Squitti

Polimanti

Bucossi

et al. 2013

Rejuvenation Research

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Copper dyshomeostasis leading to a labile Cu 2 + not bound to ceruloplasmin (''free'' copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n = 515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two ''strong LD'' blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.10-2.09, p = 0.010; rs2147363, OR = 1.58, 95% CI = 1.11-2.25, p = 0.010; rs1061472, OR = 1.73, 95% CI = 1.23-2.43, p = 0.002; rs732774, OR = 2.31, 95% CI = 1.41-3.77, p < 0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.

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Copper in Brain and Neurodegeneration

Liddell

Bush

White

2004

Encyclopedia of Inorganic and Bioinorganic Chemistry

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

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Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau

Abstract: The authors' results confirm the existence of changes in copper component distribution, particularly the copper fraction unexplained by ceruloplasmin and support the hypothesis of a beta-amyloid and copper connection in Alzheimer disease.

Cited by 173 publications

References 59 publications

Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

Ceruloplasmin fragmentation is implicated in 'free' copper deregulation of Alzheimer disease

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Copper in Brain and Neurodegeneration

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