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Homeostasis of metals in the progression of Alzheimer’s disease

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Abstract

In order to study the involvement of metals in the progression of Alzheimer’s disease, serum samples from patients with Alzheimer and mild cognitive impairment were investigated. For this purpose, metal content was analyzed after size-fractionation of species and then, inter-element and inter-fraction ratios were computed. In this way, the analysis allowed discovering changes that could be used as markers of disease, but also provided a new insight into the interactions in the homeostasis of elements in neurodegeneration and its progression. Aluminum and labile forms of iron and copper were increased in demented patients, while manganese, zinc and selenium were reduced. Interestingly, levels of different elements, principally iron, aluminum and manganese, were closely inter-related, which could evidence a complex interdependency between the homeostasis of the different metals in this disorder. On the other hand, imbalances in metabolism of copper, zinc and selenium could be associated to abnormal redox status. Therefore, this study may contribute to our understanding of the pathological mechanisms related to metals in Alzheimer’s disease.

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References

  • Ahmed SS, Santosh W (2010) Metallomic profiling and linkage map analysis of early Parkinson’s disease: a new insight to aluminum marker for the possible diagnosis. PLoS ONE 5:e11252

    Article  PubMed Central  PubMed  Google Scholar 

  • Aschner M, Guilarte TR, Schneider JS, Zheng W (2007) Manganese: recent advances in understanding its transport and neurotoxicity. Toxicol Appl Pharmacol 221:131–147

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Basun H, Forssel LG, Wetterberg L, Winblad B (1991) Metals and trace-elements in plasma and cerebrospinal-fluid in normal aging and Alzheimers-disease. J Neural Transm-Park 3:231–258

    CAS  Google Scholar 

  • Baum L, Chan IHS, Cheung SKK, Goggins WB, Mok V, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HFK, Zee BCY, Cheng W, Chan MH, Szeto S, Lui V, Tsoh J, Bush AI, Lam CWK, Kwok T (2010) Serum zinc is decreased in Alzheimer’s disease and serum arsenic correlates positively with cognitive ability. Biometals 23:173–179

    Article  CAS  PubMed  Google Scholar 

  • Berthon G (1996) Chemical speciation studies in relation to aluminium metabolism and toxicity. Coord Chem Rev 149:241–280

    Article  CAS  Google Scholar 

  • Bocca B, Alimonti A, Bomboi G, Giubilei F, Forte G (2006) Alterations in the level of trace metals in Alzheimer’s disease. Trace Elem Electrolyte 23:270–276

    Article  CAS  Google Scholar 

  • Bolognin S, Messori L, Zatta P (2009) Metal ion physiopathology in neurodegenerative disorders. NeuroMol Med 11:223–238

    Article  CAS  Google Scholar 

  • Bonda DJ, Lee HG, Blair JA, Zhu X, Perry G, Smith MA (2011) Role of metal dyshomeostasis in Alzheimer disease. Metallomics 3:267–270

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bowman AB, Kwakye GF, Hernández EH, Aschner M (2011) Role of manganese in neurodegenerative diseases. J Trace Elem Med Biol 25:191–203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bush AI, Tanzi RE (2002) The galvanization of β-amyloid in Alzheimer’s disease. Proc Natl Acad Sci USA 99:7317–7319

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bush AI, Pettingell WH, Multhaup G, Paradis M, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE (1994) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265:1464–1467

    Article  CAS  PubMed  Google Scholar 

  • Charlet L, Chapron Y, Faller P, Kirsch R, Stone AT, Baveye PC (2012) Neurodegenerative diseases and exposure to the environmental metals Mn, Pb, and Hg. Coord Chem Rev 256:2147–2163

    Article  CAS  Google Scholar 

  • Choi J, Rees HD, Weintraub ST, Levey AI, Chin LS, Li L (2005) Oxidative modifications and aggregation of Cu, Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol Chem 280:11648–11655

    Article  CAS  PubMed  Google Scholar 

  • Crapper DR, Krishnan SS, Dalton AJ (1973) Brain aluminum distribution in Alzheimer’s disease and experimental neurofibrillary degeneration. Science 180:511–513

    Article  CAS  PubMed  Google Scholar 

  • De Leo ME, Borrello S, Passantino M, Palazzotti B, Mordente A, Daniele A, Filippini V, Galeotti T, Masullo C (1998) Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer’s disease. Neurosci Lett 250:173–176

    Article  PubMed  Google Scholar 

  • Egana JT, Zambrano C, Nunez MT, Gonzalez-Billault C, Maccioni RB (2003) Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures. Biometals 16:215–223

    Article  CAS  PubMed  Google Scholar 

  • El-Ahmady O, El-Maraghy A, Ibrahim A, Ramzy S (1995) Serum copper, zinc, and iron in patients with malignant and benign pulmonary diseases. Nutrition 11:498–501

    CAS  PubMed  Google Scholar 

  • Erikson KM, Syversen T, Steinnes E, Aschner M (2004) Globus pallidus: a target brain region for divalent metal accumulation associated with dietary iron deficiency. J Nutr Biochem 15:335–341

    Article  CAS  PubMed  Google Scholar 

  • Frausto da Silva JJR, Williams RJP (2001) The biological chemistry of the elements. Oxford University Press, Oxford

    Google Scholar 

  • Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG, Hainsworth LN, Umbreit JN, Conrad ME, Feng L, Lis A, Roth JA, Singleton S, Garrick LM (2003) DMT1: a mammalian transporter for multiple metals. Biometals 16:41–54

    Article  CAS  PubMed  Google Scholar 

  • Gerhardsson L, Lundh T, Minthon L, Londos E (2008) Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 25:508–515

    Article  CAS  PubMed  Google Scholar 

  • Gerhardsson L, Lundh T, Londos E, Minthon L (2011) Cerebrospinal fluid/plasma quotients of essential and non-essential metals in patients with Alzheimer’s disease. J Neural Transm 118:957–962

    Article  CAS  PubMed  Google Scholar 

  • Han X (2010) Multi-dimensional mass spectrometry-based shotgun lipidomics and the altered lipids at the mild cognitive impairment stage of Alzheimer’s disease. Biochim Biophys Acta 1801:774–783

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5:228–234

    Article  CAS  PubMed  Google Scholar 

  • Hegde ML, Shanmugavelu P, Vengamma B, Rao TS, Menon RB, Rao RV, Rao KSJ (2004) Serum trace element levels and the complexity of inter-element relations in patients with Parkinson’s disease. J Trace Elem Med Biol 18:163–171

    Article  CAS  PubMed  Google Scholar 

  • Ihara Y, Hayabara T, Sasaki K, Fujisawa Y, Kawada R, Yamamoto T, Nakashima Y, Yoshimune S, Kawai M, Kibata M, Kuroda S (1997) Free radicals and superoxide dismutase in blood of patients with Alzheimer’s disease and vascular dementia. J Neurol Sci 153:76–81

    Article  CAS  PubMed  Google Scholar 

  • Jolly DH, Poitrinal P, Millart H, Kariger E, Blanchard F, Collery P, Choisy H (1993) Blood zinc, copper, magnesium, calcium, aluminum and manganese concentrations in patients, with or without Alzheimer-type dementia. Trace Elem Med 10:192–195

    Google Scholar 

  • Ke Y, Qian ZM (2007) Brain iron metabolism: neurobiology and neurochemistry. Prog Neurobiol 83:149–173

    Article  CAS  PubMed  Google Scholar 

  • Kiziler AR, Aydemir B, Guzel S, Alici B, Ataus S, Tuna MB, Durak H, Kilic M (2010) May the level and ratio changes of trace elements be utilized in identification of disease progression and grade in prostatic cancer? Trace Elem Electrolyte 27:65–72

    Article  CAS  Google Scholar 

  • Kovatsi L, Touliou K, Tsolaki M, Kazis A (2006) Cerebrospinal fluid levels of calcium, magnesium, copper and zinc in patients with Alzheimer’s disease and mild cognitive impairment. Trace Elem Electrolyte 23:247–250

    Article  CAS  Google Scholar 

  • Kozlowski H, Luczkowski M, Remelli M, Valensin D (2012) Copper, zinc and iron in neurodegenerative diseases (Alzheimer’s, Parkinson’s and prion diseases). Coord Chem Rev 256:2129–2141

    Article  CAS  Google Scholar 

  • Lavados M, Guillón M, Mujica MC, Rojo LE, Fuentes P, Maccioni RB (2008) Mild cognitive impairment and Alzheimer patients display different levels of redox-active CSF iron. J Alzheimers Dis 13:225–232

    CAS  PubMed  Google Scholar 

  • Loef M, Schrauzer GN, Walach H (2011) Selenium and Alzheimer’s disease: a systematic review. J Alzheimers Dis 26:81–104

    CAS  PubMed  Google Scholar 

  • Maccioni RB, Muñoz JP, Barbeito L (2001) The molecular bases of Alzheimer’s disease and other neurodegenerative diseases. Arch Med Res 32:367–381

    Article  CAS  PubMed  Google Scholar 

  • Malavolta M, Giacconi R, Piacenza F, Santarelli L, Cipriano C, Costarelli L, Tesei S, Pierpaoli S, Basso A, Galeazzi R, Lattanzio F, Mocchegiani E (2010) Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population. Biogerontology 11:309–319

    Article  CAS  PubMed  Google Scholar 

  • McGregor SJ, Brock JH, Halls D (1991) The role of transferrin and citrate in cellular uptake of aluminium. Biol Met 4:173–175

    Article  CAS  PubMed  Google Scholar 

  • McKahnn G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) 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 34:939–944

    Article  Google Scholar 

  • Mecocci P (2004) Oxidative stress in mild cognitive impairment and Alzheimer disease: a continuum. J Alzheimers Dis 6:159–163

    CAS  PubMed  Google Scholar 

  • Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L (2001) Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 58:397–405

    CAS  PubMed  Google Scholar 

  • Muñiz CS, Fernández-Martin JL, Marchante-Gayón JM, Alonso IG, Cannata-Andía JB, Sanz-Medel A (2001) Reference values for trace and ultratrace elements in human serum determined by double-focusing ICP-MS. Biol Trace Elem Res 82:259–272

    Article  PubMed  Google Scholar 

  • Mustak MS, Rao TSS, Shanmugavelu P, Sundar NMS, Menon RB, Rao RV, Rao KSJ (2008) Assessment of serum macro and trace element homeostasis and the complexity of inter-element relations in bipolar mood disorders. Clin Chim Acta 394:47–53

    Article  CAS  PubMed  Google Scholar 

  • Nischwitz V, Berthele A, Michalke B (2008) Speciation analysis of selected metals and determination of their total contents in paired serum and cerebrospinal fluid samples: an approach to investigate the permeability of the human blood-cerebrospinal fluid-barrier. Anal Chim Acta 627:258–269

    Article  CAS  PubMed  Google Scholar 

  • Núñez MT, Urrutia P, Mena N, Aguirre P, Tapia V, Salazar J (2012) Iron toxicity in neurodegeneration. Biometals 25:761–776

    Article  PubMed  Google Scholar 

  • Omar RA, Chyan YJ, Andorn AD, Poeggeler B, Robakis NK, Pappolla MA (1999) Increased expression but reduced activity of antioxidant enzymes in Alzheimer’s disease. J Alzeimers Dis 1:139–145

    CAS  Google Scholar 

  • Pérez-Parajón J, Blanco-González E, Cannata JB, Sanz-Medel A (1989) A critical appraisal of the speciation of aluminium in serum by ultrafiltration. Trace Elem Med 6:41–46

    Google Scholar 

  • Perry G, Cash AD, Srinivas R, Smith MA (2002) Metals and oxidative homeostasis in Alzheimer’s disease. Drug Develop Res 56:293–299

    Article  CAS  Google Scholar 

  • Rao JKS, Rao RV, Shanmugavelu P, Menon RB (1999) Trace elements in Alzheimer’s disease brain: a new hypothesis. Alzheimers Rep 2:241–246

    Google Scholar 

  • Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7:137–152

    Article  PubMed Central  PubMed  Google Scholar 

  • Religa D, Strozyk D, Cherny RA, Volitakis I, Haroutunian V, Winblad B, Naslund J, Bush AI (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67:69–75

    Article  CAS  PubMed  Google Scholar 

  • Rivera-Mancía S, Ríos C, Montes S (2011) Manganese accumulation in the CNS and associated pathologies. Biometals 24:811–825

    Article  PubMed  Google Scholar 

  • Roskams AJ, Connor JR (1990) Aluminium access to the brain: a role for transferrin and its receptor. Proc Natl Acad Sci USA 87:9024–9027

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sayre LM, Perry G, Atwood CS, Smith MA (2000) The role of metals in neurodegenerative diseases. Cell Mol Biol 46:731–741

    CAS  PubMed  Google Scholar 

  • Seiler HG, Sigel A, Sigel H (1994) Handbook on metals in clinical and analytical chemistry. Marcel Dekker, New York

    Google Scholar 

  • Smith Q, Rabin O, Chikhale E (1997) Delivery of metals to brain and the role of the blood-brain barrier. In: Connor J (ed) Metals and oxidative damage in neurological disorders. Plenum Press, New York, pp 113–130

    Chapter  Google Scholar 

  • Smith MA, Zhu X, Tabaton M, Liu G, McKeel DW, Cohen ML, Wang X, Siedlak SL, Dwyer BE, Hayashi T, Nakamura M, Nunomura A, Perry G (2010) Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 19:363–372

    PubMed Central  PubMed  Google Scholar 

  • Squitti R, Lupoi D, Pasqualetti P, Dal Forno G, Vernieri F, Chiovenda P, Rossi L, Cortesi M, Cassetta E, Rossini PM (2002) Elevation of serum copper levels in Alzheimer’s disease. Neurology 59:1153–1161

    Article  CAS  PubMed  Google Scholar 

  • Squitti R, Quattrocchi CC, Salustri C, Rossini PM (2008) Ceruloplasmin fragmentation is implicated in ‘free’ copper deregulation of Alzheimer’s disease. Prion 2:23–27

    Article  PubMed Central  PubMed  Google Scholar 

  • Squitti R, Ghidoni R, Scrascia F, Benussi L, Panetta V, Pasqualettia P, Moffa F, Bernardini S, Ventriglia M, Binetti G, Rossini PM (2011) Free copper distinguishes mild cognitive impairment subjects from healthy elderly individuals. J Alzheimers Dis 23:239–248

    CAS  PubMed  Google Scholar 

  • Srivastava RAK, Jain JC (2002) Scavenger receptor class B type I expression and elemental analysis in cerebellum and parietal cortex regions of the Alzheimer’s disease brain. J Neurol Sci 196:45–52

    Article  CAS  PubMed  Google Scholar 

  • Suzuki KT (2005) Metabolomics of selenium: Se metabolites based on speciation studies. J Health Sci 51:107–114

    Article  CAS  Google Scholar 

  • Templeton DM (1999) Biomedical aspects of trace element speciation. Fresenius J Anal Chem 363:505–511

    Article  CAS  Google Scholar 

  • Tomljenovic L (2011) Aluminum and Alzheimer’s disease: after a century of controversy, is there a plausible link? J Alzheimers Dis 23:567–598

    CAS  PubMed  Google Scholar 

  • Vincent JB, Love S (2012) The binding and transport of alternative metals by transferrin. Biochim Biophys Acta 1820:362–378

    Article  CAS  PubMed  Google Scholar 

  • Vural H, Sirin B, Yilmaz N, Eren I, Delibas N (2009) The role of arginine–nitric oxide pathway in patients with Alzheimer disease. Biol Trace Elem Res 129:58–64

    Article  CAS  PubMed  Google Scholar 

  • Zapatero MD, de Jalon AG, Pascual F, Calvo ML, Escanero J, Marro A (1995) Serum aluminum levels in Alzheimer’s disease and other senile dementias. Biol Trace Elem Res 47:235–240

    Article  CAS  PubMed  Google Scholar 

  • Zatta P, Cervellin D, Mattiello G, Gerotto M, Lazzari F, Gasparoni G, Gomirato L, Mazzolini G, Scarpa G, Zanoboni V, Pilone G, Favarato M (1993) Plasma multielemental analysis in Alzheimer’s disease and multi-infractual dementia. Trace Elem Med 10:85–89

    Google Scholar 

  • Zatta P, Kiss T, Suwalsky M, Berthon G (2002) Aluminium(III) as a promoter of cellular oxidation. Coord Chem Rev 228:271–284

    Article  CAS  Google Scholar 

  • Zheng W, Xin N, Chi ZH, Zhao BL, Zhang J, Li JY, Wang ZY (2009) Divalent metal transporter 1 is involved in amyloid precursor protein processing and Aβ generation. Faseb J 23:4207–4217

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the projects CTM2012-38720-C03-01 from the Ministerio de Ciencia e Innovación and P008-FQM-3554 and P009-FQM-4659 from the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía). Raúl González Domínguez thanks the Ministerio de Educación for a predoctoral scholarship. The authors also thank to Dr. Alberto Blanco and Carlos Salgado from Hospital Juan Ramón Jiménez for providing serum samples.

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  1. Department of Chemistry and CC.MM, Faculty of Experimental Science, University of Huelva, Campus de El Carmen, 21007, Huelva, Spain

    Raúl González-Domínguez, Tamara García-Barrera & José Luis Gómez-Ariza

  2. Campus of Excellence International ceiA3, University of Huelva, Huelva, Spain

    Raúl González-Domínguez, Tamara García-Barrera & José Luis Gómez-Ariza

  3. Research Center of Health and Environment (CYSMA), University of Huelva, Campus de El Carmen, 21007, Huelva, Spain

    Raúl González-Domínguez, Tamara García-Barrera & José Luis Gómez-Ariza

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  1. Raúl González-Domínguez
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  2. Tamara García-Barrera
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  3. José Luis Gómez-Ariza
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Correspondence to Tamara García-Barrera or José Luis Gómez-Ariza.

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González-Domínguez, R., García-Barrera, T. & Gómez-Ariza, J.L. Homeostasis of metals in the progression of Alzheimer’s disease. Biometals 27, 539–549 (2014). https://doi.org/10.1007/s10534-014-9728-5

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