Alzheimer’s disease (AD) is the leading cause of dementia and represents a significant burden on the global economy and society. The role of transition metals, in particular copper (Cu), in AD has become of significant interest due to the dyshomeostasis of these essential elements, which can impart profound effects on cell viability and neuronal function. We tested the hypothesis that there is a systemic perturbation in Cu compartmentalization in AD, within the brain as well as in the periphery, specifically within erythrocytes. Our results showed that the previously reported decrease in Cu within the human frontal cortex was confined to the soluble ( ) and total homogenate ( ) fractions. No differences were observed in Cu concentration in erythrocytes. Our data indicate that there is a brain specific alteration in Cu levels in AD localized to the soluble extracted material, which is not reflected in erythrocytes. Further studies using metalloproteomics approaches will be able to elucidate the metabolic mechanism(s) that results in the decreased brain Cu levels during the progression of AD. 1. Introduction Alzheimer’s disease (AD) is the predominant cause of dementia in the aging population and represents a mounting health epidemic [1]. Despite advances in understanding the events leading to the onset of cognitive decline, the principal cause of AD is still undetermined. The role of copper (Cu), iron (Fe), and zinc (Zn) in AD has become of significant interest because the dyshomeostasis of essential trace elements has been observed to have profound effects on cell viability and neuronal function [2, 3], which have been previously reviewed [4]. Cu, an essential element in the central nervous system (CNS), is crucial for life, but its unique redox propensity renders it toxic in circumstances of an increase pool of labile species [5–8]. Specific lesions in the Cu pathway can lead to a severe but treatable neurological impairment, including Menkes and Wilson’s disease [9–11]. Cu displays a distinctly compartmentalized distribution throughout the brain, reflecting its diverse function in various neurological processes [12, 13]. Within the CNS, Cu is known to decrease in the frontal, occipital, and parietal lobes [14] amygdala and hippocampus in AD [15]. The process for this decline is not well understood, though extracellular plaques of aggregated amyloid-β (Aβ) are reported to be enriched with trace elements including Fe, Zn, and Cu [16]. Recently, it was also reported that frontal cortex from AD subjects had an increased propensity to bind exchangeable Cu,
References
[1]
W. Thies and L. Bleiler, “2012 Alzheimer's disease facts and figures,” Alzheimer's and Dementia, vol. 8, no. 2, pp. 131–168, 2012.
[2]
X. Huang, R. D. Moir, R. E. Tanzi, A. I. Bush, and J. T. Rogers, “Redox-active metals, oxidative stress, and Alzheimer's disease pathology,” Annals of the New York Academy of Sciences, vol. 1012, pp. 153–163, 2004.
[3]
R. Squitti, “Metals in alzheimer's disease: a systemic perspective,” Frontiers in Bioscience, vol. 17, no. 2, pp. 451–472, 2012.
[4]
B. R. Roberts, T. M. Ryan, A. I. Bush, C. L. Masters, and J. A. Duce, “The role of metallobiology and amyloid-β peptides in Alzheimer's disease,” Journal of Neurochemistry, vol. 120, supplement 1, pp. 149–166, 2012.
[5]
H. R. Massie, V. R. Aiello, and A. A. Iodice, “Changes with age in copper and superoxide dismutase levels in brains of C57BL/6J mice,” Mechanisms of Ageing and Development, vol. 10, no. 1-2, pp. 93–99, 1979.
[6]
C. J. Maynard, R. Cappai, I. Volitakis et al., “Overexpression of Alzheimer's disease amyloid-β opposes the age-dependent elevations of brain copper and iron,” Journal of Biological Chemistry, vol. 277, no. 47, pp. 44670–44676, 2002.
[7]
S. Takahashi, I. Takahashi, H. Sato, Y. Kubota, S. Yoshida, and Y. Muramatsu, “Age-related changes in the concentrations of major and trace elements in the brain of rats and mice,” Biological Trace Element Research, vol. 80, no. 2, pp. 145–158, 2001.
[8]
E. Gaggelli, H. Kozlowski, D. Valensin, and G. Valensin, “Copper homeostasis and neurodegenerative disorders (Alzheimer's, prion, and Parkinson's diseases and amyotrophic lateral sclerosis),” Chemical Reviews, vol. 106, no. 6, pp. 1995–2044, 2006.
[9]
J. F. B. Mercer, J. Livingston, B. Hall et al., “Isolation of partial candidate gene for Menkes disease by positional cloning,” Nature Genetics, vol. 3, no. 1, pp. 20–25, 1993.
[10]
N. Gouider-Khouja, “Wilson's disease,” Parkinsonism and Related Disorders, vol. 15, no. 3, pp. S126–S129, 2009.
[11]
D. J. Waggoner, T. B. Bartnikas, and J. D. Gitlin, “The role of copper in neurodegenerative disease,” Neurobiology of Disease, vol. 6, no. 4, pp. 221–230, 1999.
[12]
D. J. Hare, J. K. Lee, A. D. Beavis et al., “Three-dimensional atlas of iron, copper, and zinc in the mouse cerebrum and brainstem,” Analytical Chemistry, vol. 84, no. 9, pp. 3990–3997, 2012.
[13]
K. M. Davies, D. J. Hare, V. Cottam, et al., “Localization of copper and copper transporters in the human brain,” Metallomics, vol. 5, no. 1, pp. 43–51, 2013.
[14]
L. O. Plantin, U. Lying-Tunell, and K. Kristensson, “Trace elements in the human central nervous system studied with neutron activation analysis,” Biological Trace Element Research, vol. 13, no. 1, pp. 69–75, 1987.
[15]
M. A. Deibel, W. D. Ehmann, and W. R. Markesbery, “Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress,” Journal of the Neurological Sciences, vol. 143, no. 1-2, pp. 137–142, 1996.
[16]
A. Tiiman, P. Palumaa, and V. Tougu, “The missing link in the amyloid cascade of Alzheimer's disease—metal ions,” Neurochemistry International, vol. 62, no. 4, pp. 367–378, 2013.
[17]
S. A. James, I. Volitakis, P. A. Adlard et al., “Elevated labile Cu is associated with oxidative pathology in Alzheimer disease,” Free Radical Biology and Medicine, vol. 52, no. 2, pp. 298–302, 2012.
[18]
C. R. Capo, M. Arciello, R. Squitti et al., “Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer's disease patients,” BioMetals, vol. 21, no. 3, pp. 367–372, 2008.
[19]
S. Bucossi, M. Ventriglia, V. Panetta et al., “Copper in alzheimer's disease: a meta-analysis of serum,plasma, and cerebrospinal fluid studies,” Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 175–185, 2011.
[20]
S. Bucossi, M. Ventriglia, V. Panetta et al., “Copper in alzheimer's disease: a meta-analysis of serum,plasma, and cerebrospinal fluid studies,” Journal of Alzheimer's Disease, vol. 24, no. 1, pp. 175–185, 2011.
[21]
R. Squitti, D. Lupoi, P. Pasqualetti et al., “Elevation of serum copper levels in Alzheimer's disease,” Neurology, vol. 59, no. 8, pp. 1153–1161, 2002.
[22]
G. J. Brewer, S. H. Kanzer, E. A. Zimmerman, D. F. Celmins, S. M. Heckman, and R. Dick, “Copper and ceruloplasmin abnormalities in Alzheimers disease,” American Journal of Alzheimer's Disease and other Dementias, vol. 25, no. 6, pp. 490–497, 2010.
[23]
H. Vural, H. Demirin, Y. Kara, I. Eren, and N. Delibas, “Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer's disease,” Journal of Trace Elements in Medicine and Biology, vol. 24, no. 3, pp. 169–173, 2010.
[24]
J. A. Molina, F. J. Jiménez-Jiménez, M. V. Aguilar et al., “Cerebrospinal fluid levels of transition metals in patients with Alzheimer's disease,” Journal of Neural Transmission, vol. 105, no. 4-5, pp. 479–488, 1998.
[25]
R. Ozcankaya and N. Delibas, “Malondialdehyde, superoxide dismutase, melatonin, iron, copper, and zinc blood concentrations in patients with Alzheimer disease: cross-sectional study,” Croatian Medical Journal, vol. 43, no. 1, pp. 28–32, 2002.
[26]
B. S. Sedighi and M. Shariati, “A study of serum copper and ceruloplasmin in Alzheimer’s disease in Kerman, Iran,” Neurology Asia, vol. 11, pp. 107–109, 2006.
[27]
R. Squitti, “Copper dysfunction in Alzheimer's disease: from meta-analysis of biochemical studies to new insight into genetics,” Journal of Trace Elements in Medicine and Biology, vol. 26, no. 2-3, pp. 93–96, 2012.
[28]
R. Squitti, R. Ghidoni, F. Scrascia et al., “Free copper distinguishes mild cognitive impairment subjects from healthy elderly individuals,” Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 239–248, 2011.
[29]
R. Squitti, P. Pasqualetti, E. Cassetta et al., “Elevation of serum copper levels discriminates Alzheimer's disease from vascular dementia,” Neurology, vol. 60, no. 12, pp. 2013–2014, 2003.
[30]
R. Squitti, E. Cassetta, G. Dal Forno et al., “Copper perturbation in 2 monozygotic twins discordant for degree of cognitive impairment,” Archives of Neurology, vol. 61, no. 5, pp. 738–743, 2004.
[31]
R. Squitti, P. Pasqualetti, G. Dal Forno et al., “Excess of serum copper not related to ceruloplasmin in Alzheimer disease,” Neurology, vol. 64, no. 6, pp. 1040–1046, 2005.
[32]
R. Squitti, G. Barbati, L. Rossi et al., “Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau,” Neurology, vol. 67, no. 1, pp. 76–82, 2006.
[33]
R. Squitti, F. Bressi, P. Pasqualetti et al., “Longitudinal prognostic value of serum “free” copper in patients with Alzheimer disease,” Neurology, vol. 72, no. 1, pp. 50–55, 2009.
[34]
C. Salustri, R. Squitti, F. Zappasodi et al., “Oxidative stress and brain glutamate-mediated excitability in depressed patients,” Journal of Affective Disorders, vol. 127, no. 1–3, pp. 321–325, 2010.
[35]
A. Rembach, J. D. Doecke, B. R. Roberts, et al., “Longitudinal analysis of serum copper and ceruloplasmin in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 171–182, 2013.
[36]
L. M. Klevay, “Alzheimer's disease as copper deficiency,” Medical Hypotheses, vol. 70, no. 4, pp. 802–807, 2008.
[37]
K. A. Ellis, A. I. Bush, D. Darby et al., “The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease,” International Psychogeriatrics, vol. 21, no. 4, pp. 672–687, 2009.
[38]
R. C. Petersen, G. E. Smith, S. C. Waring, R. J. Ivnik, E. G. Tangalos, and E. Kokmen, “Mild cognitive impairment: clinical characterization and outcome,” Archives of Neurology, vol. 56, no. 3, pp. 303–308, 1999.
[39]
B. Winblad, K. Palmer, M. Kivipelto et al., “Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment,” Journal of Internal Medicine, vol. 256, no. 3, pp. 240–246, 2004.
[40]
G. McKhann, D. Drachman, and M. Folstein, “Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease,” Neurology, vol. 34, no. 7, pp. 939–944, 1984.
[41]
C. L. Masters, G. Simms, and N. A. Weinman, “Amyloid plaque core protein in Alzheimer disease and Down syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 12, pp. 4245–4249, 1985.
[42]
D. A. Butterfield, B. T. Farmer II, and W. R. Markesbery, “Alzheimer's disease: no alteration in the physical state of erythrocyte membrane glycoconjugates,” Annals of Neurology, vol. 18, no. 1, pp. 104–105, 1985.
[43]
J. G. Mohanty, H. D. Shukla, J. D. Williamson, L. J. Launer, S. Saxena, and J. M. Rifkind, “Alterations in the red blood cell membrane proteome in alzheimer's subjects reflect disease-related changes and provide insight into altered cell morphology,” Proteome Science, vol. 8, article 11, 2010.
[44]
M. Schrag, C. Mueller, U. Oyoyo, M. A. Smith, and W. M. Kirsch, “Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion,” Progress in Neurobiology, vol. 94, no. 3, pp. 296–306, 2011.
[45]
D. Wenstrup, W. D. Ehmann, and W. R. Markesbery, “Trace element imbalances in isolated subcellular fractions of Alzheimer's disease brains,” Brain Research, vol. 533, no. 1, pp. 125–131, 1990.
[46]
Y. Uchida, K. Takio, K. Titani, Y. Ihara, and M. Tomonaga, “The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein,” Neuron, vol. 7, no. 2, pp. 337–347, 1991.
[47]
A.-N. Richarz and P. Br？tter, “Speciation analysis of trace elements in the brains of individuals with Alzheimer's disease with special emphasis on metallothioneins,” Fresenius' Journal of Analytical Chemistry, vol. 372, no. 3, pp. 412–417, 2002.
[48]
M. A. Lovell, J. D. Robertson, W. J. Teesdale, J. L. Campbell, and W. R. Markesbery, “Copper, iron and zinc in Alzheimer's disease senile plaques,” Journal of the Neurological Sciences, vol. 158, no. 1, pp. 47–52, 1998.
[49]
L. M. Miller, Q. Wang, T. P. Telivala, R. J. Smith, A. Lanzirotti, and J. Miklossy, “Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with β-amyloid deposits in Alzheimer's disease,” Journal of Structural Biology, vol. 155, no. 1, pp. 30–37, 2006.
[50]
S. A. James, M. D. De Jonge, D. L. Howard, A. I. Bush, D. Paterson, and G. Mccoll, “Direct in vivo imaging of essential bioinorganics in Caenorhabditis elegans,” Metallomics, vol. 5, no. 6, pp. 627–635, 2013.
[51]
D. J. Hare, J. L. George, R. Grimm et al., “Three-dimensional elemental bio-imaging of Fe, Zn, Cu, Mn and P in a 6-hydroxydopamine lesioned mouse brain,” Metallomics, vol. 2, no. 11, pp. 745–753, 2010.
[52]
R. W. Hutchinson, A. G. Cox, C. W. McLeod et al., “Imaging and spatial distribution of β-amyloid peptide and metal ions in Alzheimer's plaques by laser ablation-inductively coupled plasma-mass spectrometry,” Analytical Biochemistry, vol. 346, no. 2, pp. 225–233, 2005.
[53]
L. Banci, I. Bertini, S. Ciofi-Baffoni, T. Kozyreva, K. Zovo, and P. Palumaa, “Affinity gradients drive copper to cellular destinations,” Nature, vol. 465, no. 7298, pp. 645–648, 2010.
[54]
W. Thies and L. Bleiler, “2011 Alzheimer's disease facts and figures,” Alzheimer's and Dementia, vol. 7, no. 2, pp. 208–244, 2011.
[55]
T. D. Rae, P. J. Schmidt, R. A. Pufahl, V. C. Culotta, and T. V. O'Halloran, “Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase,” Science, vol. 284, no. 5415, pp. 805–808, 1999.
[56]
A. Cvetkovic, A. L. Menon, M. P. Thorgersen et al., “Microbial metalloproteomes are largely uncharacterized,” Nature, vol. 466, no. 7307, pp. 779–782, 2010.
[57]
W. A. Lancaster, J. L. Praissman, F. L. Poole II et al., “A Computational framework for proteome-wide pursuit and prediction of metalloproteins using ICP-MS and MS/MS data,” BMC Bioinformatics, vol. 12, article 64, 2011.
[58]
A. Lothian, D. J. Hare, R. Grimm, T. M. Ryan, C. L. Masters, and B. R. Roberts, “Metalloproteomics: principles, challenges and applications to neurodegeneration,” Frontiers in Aging Neuroscience, vol. 5, p. 35, 2013.
