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An overview of various mammalian models to study chronic copper intoxication associated Alzheimer’s disease like pathology

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Abstract

Chronic copper toxicity has been long known to cause hepatotoxicity and liver cirrhosis as observed in Wilson’s disease; however, substantial evidence accrued over the time have shown considerable increase in animal studies demonstrating Alzheimer’s disease like pathology due to chronic copper-intoxication under certain conditions. This review integrates the contemporary mammalian studies in which the effect of chronic copper intoxication was assessed on the central nervous system and cognition of animals.

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References

  • An L, Liu S, Yang Z, Zhang T (2012) Cognitive impairment in rats induced by nano-CuO and its possible mechanisms. Toxicol Lett 213(2):220–227

    Article  CAS  PubMed  Google Scholar 

  • Arcaya JL, Tejeda CM, Salazar U, Silva EJ, Urdaneta K, Varela K (2013) Copper intoxication decreases lifespan and induces neurologic alterations in Drosophila melanogaster. Investig Clin 54(1):47–57

    Google Scholar 

  • Arnal N, Castillo O, de Alaniz MJ, Marra CA (2013a) Effects of copper and/or cholesterol overload on mitochondrial function in a rat model of incipient neurodegeneration. Int J Alzheimers Dis 2013:645379. doi:10.1155/2013/645379

    PubMed Central  PubMed  Google Scholar 

  • Arnal N, Morel GR, de Alaniz MJ, Castillo O, Marra CA (2013b) Role of copper and cholesterol association in the neurodegenerative process. Int J Alzheimers Dis 2013:414817

    PubMed Central  PubMed  Google Scholar 

  • Arnal N, Dominici L, de Tacconi MJ, Marra CA (2014) Copper-induced alterations in rat brain depends on route of overload and basal copper levels. Nutrition 30(1):96–106

    Article  CAS  PubMed  Google Scholar 

  • Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI (1998) Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 273(21):12817–12826

    Article  CAS  PubMed  Google Scholar 

  • Bremner I (1998) Manifestations of copper excess. Am J Clin Nutr 67:1069S–1073S

  • Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5(4):327–337

    Article  CAS  PubMed  Google Scholar 

  • Butterworth RF (2010) Metal toxicity, liver disease and neurodegeneration. Neurotox Res 18(1):100–105

    Article  PubMed  Google Scholar 

  • Carri MT, Ferri A, Cozzolino M, Calabrese L, Rotilio G (2003) Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Brain Res Bull 61(4):365–374

    Article  CAS  PubMed  Google Scholar 

  • Choi BS, Zheng W (2009) Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res 1248:14–21

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Desai V, Kaler SG (2008) Role of copper in human neurological disorders. Am J Clin Nutr 88(3):855S–858S

    CAS  PubMed  Google Scholar 

  • Eskici G, Axelsen PH (2012) Copper and oxidative stress in the pathogenesis of Alzheimer’s disease. Biochemistry 51(32):6289–6311

    Article  CAS  PubMed  Google Scholar 

  • European Association for Study of Liver (2012) EASL clinical practice guidelines: wilson’s disease. J Hepatol 56(3):671–685

    Google Scholar 

  • Fuentealba IC, Aburto EM (2003) Animal models of copper-associated liver disease. Comp Hepatol 2(1):5

    Article  PubMed Central  PubMed  Google Scholar 

  • Fujiwara N, Iso H, Kitanaka N, Kitanaka J, Eguchi H, Ookawara T, Ozawa K, Shimoda S, Yoshihara D, Takemura M, Suzuki K (2006) Effects of copper metabolism on neurological functions in Wistar and Wilson’s disease model rats. Biochem Biophys Res Commun 349(3):1079–1086

    Article  CAS  PubMed  Google Scholar 

  • Halatek T, Lutz P, Krajnow A, Stetkiewicz J, Domeradzka K, Swiercz R, Wasowicz W (2011) Assessment of neurobehavioral and biochemical effects in rats exposed to copper smelter dusts. J Environ Sci Health A Tox Hazard Subst Environ Eng 46(3):230–241

    Article  CAS  PubMed  Google Scholar 

  • He JL, Zhu SL, Wu P, Li PP, Li T, Cao Z (2014) Enzymatic cascade based fluorescent DNAzyme machines for the ultrasensitive detection of Cu(II) ions. Biosens Bioelectron 60C:112–117

    Article  Google Scholar 

  • Hirayama T, Van de Bittner GC, Gray LW, Lutsenko S, Chang CJ (2012) Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model. Proc Natl Acad Sci U S A 109(7):2228–2233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jain S, Scheuer PJ, Archer B, Newman SP, Sherlock S (1978) Histological demonstration of copper and copper-associated protein in chronic liver diseases. J Clin Pathol 31(8):784–790

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kaler SG (2011) ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol 7(1):15–29

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leiva J, Palestini M, Infante C, Goldschmidt A, Motles E (2009) Copper suppresses hippocampus LTP in the rat, but does not alter learning or memory in the morris water maze. Brain Res 1256:69–75

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Zheng YL, Wu DM, Sun DX, Shan Q, Fan SH (2006) Trace amounts of copper induce neurotoxicity in the cholesterol-fed mice through apoptosis. FEBS Lett 580(28–29):6730–6740

    Article  CAS  PubMed  Google Scholar 

  • Mao X, Ye J, Zhou S, Pi R, Dou J, Zang L, Chen X, Chao X, Li W, Liu M, Liu P (2012) The effects of chronic copper exposure on the amyloid protein metabolisim associated genes’ expression in chronic cerebral hypoperfused rats. Neurosci Lett 518(1):14–18

    Article  CAS  PubMed  Google Scholar 

  • Monnot AD, Behl M, Ho S, Zheng W (2011) Regulation of brain copper homeostasis by the brain barrier systems: effects of Fe-overload and Fe-deficiency. Toxicol Appl Pharmacol 256(3):249–257

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Narasaki M (1980) Laboratory and histological similarities between Wilson’s disease and rats with copper toxicity. Acta Med Okayama 34(2):81–90

    CAS  PubMed  Google Scholar 

  • Ozcelik D, Uzun H (2009) Copper intoxication; antioxidant defenses and oxidative damage in rat brain. Biol Trace Elem Res 127(1):45–52

    Article  CAS  PubMed  Google Scholar 

  • Pal A (2014) Copper toxicity induced hepatocerebral and neurodegenerative diseases: an urgent need for prognostic biomarkers. Neurotoxicology 40C:97–101

    Article  Google Scholar 

  • Pal A, Prasad R (2014) Recent discoveries on the functions of astrocytes in the copper homeostasis of the brain: a brief update. Neurotox Res 26:78–84

  • Pal A, Badyal RK, Vasishta RK, Attri SV, Thapa BR, Prasad R (2013a) Biochemical, histological, and memory impairment effects of chronic copper toxicity: a model for non-wilsonian brain copper toxicosis in wistar rat. Biol Trace Elem Res 153(1–3):257–268

    Article  CAS  PubMed  Google Scholar 

  • Pal A, Vasishta RK, Prasad R (2013b) Hepatic and hippocampus iron status is not altered in response to increased serum ceruloplasmin and serum “free” copper in Wistar rat model for non-Wilsonian brain copper toxicosis. Biol Trace Elem Res 154(3):403–411

    Article  CAS  PubMed  Google Scholar 

  • Pal A, Kumar A, Prasad R (2014) Predictive association of copper metabolism proteins with Alzheimer’s disease and Parkinson’s disease: a preliminary perspective. Biometals. doi:10.1007/s10534-013-9702-7

    Google Scholar 

  • Peng F, Lutsenko S, Sun X, Muzik O (2012) Imaging copper metabolism imbalance in Atp7b (-/-) knockout mouse model of Wilson’s disease with PET-CT and orally administered 64CuCl2. Mol Imaging Biol 14(5):600–607

    Article  PubMed  Google Scholar 

  • Que EL, Domaille DW, Chang CJ (2008) Metals in neurobiology: probing their chemistry and biology with molecular imaging. Chem Rev 108(5):1517–1549

    Article  CAS  PubMed  Google Scholar 

  • Reddy PV, Rao KV, Norenberg MD (2008) The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes. Lab Investig 88(8):816–830

    Article  CAS  PubMed  Google Scholar 

  • Roberts EA, Schilsky ML, American Association for Study of Liver D (2008) Diagnosis and treatment of Wilson disease: an update. Hepatology 47(6):2089–2111

    Article  CAS  PubMed  Google Scholar 

  • Scheiber IF, Mercer JF, Dringen R (2014) Metabolism and functions of copper in brain. Prog Neurobiol. doi:10.1016/j.pneurobio.2014.01.002

    PubMed  Google Scholar 

  • Singh I, Sagare AP, Coma M, Perlmutter D, Gelein R, Bell RD, Deane RJ, Zhong E, Parisi M, Ciszewski J, Kasper RT, Deane R (2013) Low levels of copper disrupt brain amyloid-beta homeostasis by altering its production and clearance. Proc Natl Acad Sci USA 110(36):14771–14776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sparks DL (2008) The early and ongoing experience with the cholesterol-fed rabbit as a model of Alzheimer’s disease: the old, the new and the pilot. J Alzheimers Dis 15(4):641–656

    CAS  PubMed  Google Scholar 

  • Sparks DL, Schreurs BG (2003) Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease. Proc Natl Acad Sci USA 100(19):11065–11069

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sparks DL, Friedland R, Petanceska S, Schreurs BG, Shi J, Perry G, Smith MA, Sharma A, Derosa S, Ziolkowski C, Stankovic G (2006) Trace copper levels in the drinking water, but not zinc or aluminum influence CNS Alzheimer-like pathology. J Nutr Health Aging 10(4):247–254

    CAS  PubMed Central  PubMed  Google Scholar 

  • Squitti R, Barbati G, Rossi L, Ventriglia M, Forno GD, Cesaretti S, Moffa F, Caridi I, Cassetta E, Pasqualetti P, Calabrese L, Lupoi D, Rossini PM (2006) Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau. Neurology 67(1):76–82

    Article  CAS  PubMed  Google Scholar 

  • Squitti R, Bressi F, Pasqualetti P, Bonomini C, Ghidoni R, Binetti G, Cassetta E, Moffa F, Ventriglia M, Vernieri F, Rossini PM (2009) Longitudinal prognostic value of serum “free” copper in patients with Alzheimer disease. Neurology 72(1):50–55

    Article  CAS  PubMed  Google Scholar 

  • Squitti R, Ghidoni R, Siotto M, Ventriglia M, Benussi L, Paterlini A, Magri M, Binetti G, Cassetta E, Caprara D, Vernieri F, Rossini PM, Pasqualetti P (2014a) Value of serum non-ceruloplasmin copper for prediction of MCI conversion to AD. Ann Neurol. doi:10.1002/ana.24136

    PubMed  Google Scholar 

  • Squitti R, Simonelli I, Ventriglia M, Siotto M, Pasqualetti P, Rembach A, Doecke J, Bush AI (2014b) Meta-analysis of serum non-ceruloplasmin copper in Alzheimer’s disease. J Alzheimers Dis 38(4):809–822

    CAS  PubMed  Google Scholar 

  • Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, Romano DM, Parano E, Pavone L, Brzustowicz LM et al (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5(4):344–350

    Article  CAS  PubMed  Google Scholar 

  • Terwel D, Loschmann YN, Schmidt HH, Scholer HR, Cantz T, Heneka MT (2011) Neuroinflammatory and behavioural changes in the Atp7B mutant mouse model of Wilson’s disease. J Neurochem 118(1):105–112

    Article  CAS  PubMed  Google Scholar 

  • Tiffany-Castiglioni E, Hong S, Qian Y (2011) Copper handling by astrocytes: insights into neurodegenerative diseases. Int J Dev Neurosci 29(8):811–818

    Article  CAS  PubMed  Google Scholar 

  • U. S. Environmental Protection Agency (1994) Federal Register 59:33860–33864.

  • Vogt S, Ralle M (2013) Opportunities in multidimensional trace metal imaging: taking copper-associated disease research to the next level. Anal Bioanal Chem 405(6):1809–1820

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vonk WI, Wijmenga C, van de Sluis B (2008) Relevance of animal models for understanding mammalian copper homeostasis. Am J Clin Nutr 88(3):840S–845S

    CAS  PubMed  Google Scholar 

  • White AR, Reyes R, Mercer JF, Camakaris J, Zheng H, Bush AI, Multhaup G, Beyreuther K, Masters CL, Cappai R (1999) Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res 842(2):439–444

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Chen Y, Lin Z, Li Q, Peng L, Han M (2014) Ultrasonic oscillation dialysis-graphite furnace atomic absorption spectrometer method for determination of “free” copper and exchangeable copper in serum. Clin Lab 60(4):543–551

    CAS  PubMed  Google Scholar 

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Acknowledgments

The financial assistance in the form of JRF/SRF to Dr. Amit Pal [3/1/3/JRF-2009/HRD-13 (11279)] by the Indian Council of medical Research, New Delhi, is acknowledged by the authors. For this review, the authors apologize to any researcher whose work was not cited because of length constraints.

Conflict of interest

None declared.

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  1. Department of Biochemistry, PGIMER, Chandigarh, 160012, India

    Amit Pal & Rajendra Prasad

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  1. Amit Pal
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Correspondence to Rajendra Prasad.

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Pal, A., Prasad, R. An overview of various mammalian models to study chronic copper intoxication associated Alzheimer’s disease like pathology. Biometals 28, 1–9 (2015). https://doi.org/10.1007/s10534-014-9799-3

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