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Concentration-dependent effects of mercury and lead on Aβ42: possible implications for Alzheimer’s disease

  • Daniela MeleleoEmail author
  • Gabriella Notarachille
  • Vincenzo Mangini
  • Fabio Arnesano
Original Article

Abstract

Mercury (Hg) and lead (Pb) are known to be toxic non-radioactive elements, with well-described neurotoxicology. Much evidence supports the implication of metals as potential risk cofactors in Alzheimer’s disease (AD). Although the action mechanism of the two metals remains unclear, Hg and Pb toxicity in AD could depend on their ability to favour misfolding and aggregation of amyloid beta proteins (Aβs) that seem to have toxic properties, particularly in their aggregated state. In our study, we evaluated the effect of Hg and Pb both on the Aβ42 ion channel incorporated in a planar lipid membrane made up of phosphatidylcholine containing 30% cholesterol and on the secondary structure of Aβ42 in an aqueous environment. The effects of Hg and Pb on the Aβ42 peptide were observed for its channel incorporated into a membrane as well as for the peptide in solution. A decreasing Aβ42 channel frequency and the formation of large and amorphous aggregates in solution that are prone to precipitate were both dependent on metal concentration. These experimental data suggest that Hg and Pb interact directly with Aβs, strengthening the hypothesis that the two metals may be a risk factor in AD.

Keywords

Aβ Ion channel Lipid bilayer Aggregation Mercury Lead 

Notes

Acknowledgements

The authors acknowledge Dr. Antonio Rosato and Maria Incoronata Nardella for their assistance in the recording of CD spectra. The University of Bari and the Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB) are gratefully acknowledged for their support for this work. The authors acknowledge Anthony Green for proofreading and providing linguistic advice.

Compliance with ethical standards

Conflict of interest

The authors declare that they do not have a conflict of interest.

References

  1. Arispe N, Rojas E, Pollard H (1993) Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci USA 90(2):567–571PubMedGoogle Scholar
  2. Atwood C, Moir R, Huang X, Scarpa R, Bacarra N, Romano D, Hartshorn M, Tanzi R, Bush A (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 273(21):12817–12826PubMedGoogle Scholar
  3. Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI (2000) Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1–42. J Neurochem 75(3):1219–1233PubMedGoogle Scholar
  4. Basha MR, Murali M, Siddiqi HK, Ghosal K, Siddiqi OK, Lashuel HA, Ge YW, Lahiri DK, Zawia NH (2005a) Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation. FASEB J 19(14):2083–2084PubMedGoogle Scholar
  5. Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH (2005b) The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 25(4):823–829PubMedGoogle Scholar
  6. Bihaqi SW, Huang H, Wu J, Zawia NH (2011) Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: implications for Alzheimer’s disease. J Alzheimers Dis 27(4):819–833PubMedGoogle Scholar
  7. Bihaqi SW, Bahmani A, Subaiea GM, Zawia NH (2014) Infantile exposure to lead and late-age cognitive decline: relevance to AD. Alzheimers Dement 10(2):187–195PubMedGoogle Scholar
  8. Bihaqi SW, Eid A, Zawia NH (2017) Lead exposure and tau hyperphosphorylation: an in vitro study. Neurotoxicology 62:218–223PubMedGoogle Scholar
  9. Bocharova OV, Breydo L, Salnikov VV, Baskakov IV (2005) Copper(II) inhibits in vitro conversion of prion protein into amyloid fibrils. Biochemistry 44(18):6776–6787PubMedGoogle Scholar
  10. Bode DC, Baker MD, Viles JH (2017) Ion channel formation by amyloid-β42 oligomers but not amyloid-β40 in cellular membranes. J Biol Chem 292(4):1404–1413PubMedGoogle Scholar
  11. Bush A (2000) Metals and neuroscience. Curr Opin Chem Biol 4(2):184–191PubMedGoogle Scholar
  12. Bush AI, Pettingell WH, Multhaup G, Paradis MD, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE (1994a) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265(5177):1464–1467PubMedGoogle Scholar
  13. Bush AI, Pettingell WH, Paradis MD, Tanzi RE (1994b) Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem 269(16):12152–12158PubMedGoogle Scholar
  14. Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298PubMedGoogle Scholar
  15. Chauhan V, Chauhan A (2006) Oxidative stress in Alzheimer’s disease. Pathophysiology 13(3):195–208PubMedGoogle Scholar
  16. Chi EY, Ege C, Winans A, Majewski J, Wu G, Kjaer K, Lee KY (2008) Lipid membrane templates the ordering and induces the fibrillogenesis of Alzheimer’s disease amyloid-beta peptide. Proteins 72(1):1–24PubMedGoogle Scholar
  17. Davis CH, Berkowitz ML (2010) A molecular dynamics study of the early stages of amyloid-beta(1-42) oligomerization: the role of lipid membranes. Proteins 78(11):2533–2545PubMedPubMedCentralGoogle Scholar
  18. de Planque MR, Raussens V, Contera SA, Rijkers DT, Liskamp RM, Ruysschaert JM, Ryan JF, Separovic F, Watts A (2007) beta-Sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes. J Mol Biol 368(4):982–997PubMedGoogle Scholar
  19. Di Carlo M (2010) Beta amyloid peptide: from different aggregation forms to the activation of different biochemical pathways. Eur Biophys J 39(6):877–888PubMedGoogle Scholar
  20. Eid A, Bihaqi SW, Renehan WE, Zawia NH (2016) Developmental lead exposure and lifespan alterations in epigenetic regulators and their correspondence to biomarkers of Alzheimer’s disease. Alzheimers Dement (Amst) 2:123–131Google Scholar
  21. Fujimura M, Usuki F (2012) Differing effects of toxicants (methylmercury, inorganic mercury, lead, amyloid β, and rotenone) on cultured rat cerebrocortical neurons: differential expression of rho proteins associated with neurotoxicity. Toxicol Sci 126(2):506–514PubMedGoogle Scholar
  22. Fukumoto H, Tokuda T, Kasai T, Ishigami N, Hidaka H, Kondo M, Allsop D, Nakagawa M (2010) High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J 24(8):2716–2726PubMedGoogle Scholar
  23. Gallucci E, Meleleo D, Micelli S, Picciarelli V (2003) Magainin 2 channel formation in planar lipid membranes: the role of lipid polar groups and ergosterol. Eur Biophys J 32(1):22–32PubMedGoogle Scholar
  24. 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(6):508–515PubMedGoogle Scholar
  25. Glabe CG (2006) Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging 27(4):570–575PubMedGoogle Scholar
  26. Hirakura Y, Lin M, Kagan B (1999) Alzheimer amyloid abeta1-42 channels: effects of solvent, pH, and Congo Red. J Neurosci Res 57(4):458–466PubMedGoogle Scholar
  27. Hock C, Drasch G, Golombowski S, Müller-Spahn F, Willershausen-Zönnchen B, Schwarz P, Hock U, Growdon JH, Nitsch RM (1998) Increased blood mercury levels in patients with Alzheimer’s disease. J Neural Transm (Vienna) 105(1):59–68Google Scholar
  28. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI (1999) Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 274(52):37111–37116PubMedGoogle Scholar
  29. Jarrett JT, Berger EP, Lansbury PT (1993) The C-terminus of the beta protein is critical in amyloidogenesis. Ann N Y Acad Sci 695:144–148PubMedGoogle Scholar
  30. Kim DK, Park JD, Choi BS (2014) Mercury-induced amyloid-beta (Aβ) accumulation in the brain is mediated by disruption of Aβ transport. J Toxicol Sci 39(4):625–635PubMedGoogle Scholar
  31. LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8(7):499–509PubMedGoogle Scholar
  32. Lambert M, Barlow A, Chromy B, Edwards C, Freed R, Liosatos M, Morgan T, Rozovsky I, Trommer B, Viola K, Wals P, Zhang C, Finch C, Krafft G, Klein W (1998) Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95(11):6448–6453PubMedGoogle Scholar
  33. Lesné S, Kotilinek L, Ashe KH (2008) Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience 151(3):745–749PubMedGoogle Scholar
  34. Lue L, Kuo Y, Roher A, Brachova L, Shen Y, Sue L, Beach T, Kurth J, Rydel R, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155(3):853–862PubMedPubMedCentralGoogle Scholar
  35. Masoud AM, Bihaqi SW, Machan JT, Zawia NH, Renehan WE (2016) Early-life exposure to lead (Pb) alters the expression of microRNA that target proteins associated with Alzheimer’s disease. J Alzheimers Dis 51(4):1257–1264PubMedGoogle Scholar
  36. May PC, Gitter BD, Waters DC, Simmons LK, Becker GW, Small JS, Robison PM (1992) beta-Amyloid peptide in vitro toxicity: lot-to-lot variability. Neurobiol Aging 13(5):605–607PubMedGoogle Scholar
  37. McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K, Bush A, Masters C (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46(6):860–866PubMedGoogle Scholar
  38. Meleleo D, Galliani A, Notarachille G (2013) AβP1-42 incorporation and channel formation in planar lipid membranes: the role of cholesterol and its oxidation products. J Bioenerg Biomembr 45(4):369–381PubMedGoogle Scholar
  39. Micelli S, Gallucci E, Meleleo D, Stipani V, Picciarelli V (2002) Mitochondrial porin incorporation into black lipid membranes: ionic and gating contribution to the total current. Bioelectrochemistry 57(2):97–106PubMedGoogle Scholar
  40. Micelli S, Meleleo D, Picciarelli V, Gallucci E (2004) Effect of sterols on beta-amyloid peptide (AbetaP 1–40) channel formation and their properties in planar lipid membranes. Biophys J 86(4):2231–2237PubMedPubMedCentralGoogle Scholar
  41. Minicozzi V, Stellato F, Comai M, Dalla Serra M, Potrich C, Meyer-Klaucke W, Morante S (2008) Identifying the minimal copper- and zinc-binding site sequence in amyloid-beta peptides. J Biol Chem 283(16):10784–10792PubMedGoogle Scholar
  42. Müller P, Rudin D, Tien T, Weacott W (1962) Reconstitution of cell membrane structure in vitro and its trasformation into an excitable system. Nature 194:979–980Google Scholar
  43. Mutter J, Naumann J, Sadaghiani C, Schneider R, Walach H (2004) Alzheimer disease: mercury as pathogenetic factor and apolipoprotein E as a moderator. Neuro Endocrinol Lett 25(5):331–339PubMedGoogle Scholar
  44. Mutter J, Curth A, Naumann J, Deth R, Walach H (2010) Does inorganic mercury play a role in Alzheimer’s disease? A systematic review and an integrated molecular mechanism. J Alzheimers Dis 22(2):357–374PubMedGoogle Scholar
  45. Nelson TJ, Alkon DL (2005) Oxidation of cholesterol by amyloid precursor protein and beta-amyloid peptide. J Biol Chem 280(8):7377–7387PubMedGoogle Scholar
  46. Notarachille G, Arnesano F, Calò V, Meleleo D (2014) Heavy metals toxicity: effect of cadmium ions on amyloid beta protein 1–42. Possible implications for Alzheimer’s disease. Biometals 27(2):371–388PubMedGoogle Scholar
  47. Olivieri G, Brack C, Müller-Spahn F, Stähelin HB, Herrmann M, Renard P, Brockhaus M, Hock C (2000) Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J Neurochem 74(1):231–236PubMedGoogle Scholar
  48. Olivieri G, Novakovic M, Savaskan E, Meier F, Baysang G, Brockhaus M, Müller-Spahn F (2002) The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion. Neuroscience 113(4):849–855PubMedGoogle Scholar
  49. Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi RE, Inestrosa NC, Bush AI (2002) Metalloenzyme-like activity of Alzheimer’s disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem 277(43):40302–40308PubMedGoogle Scholar
  50. Palkiewicz P, Zwiers H, Lorscheider FL (1994) ADP-ribosylation of brain neuronal proteins is altered by in vitro and in vivo exposure to inorganic mercury. J Neurochem 62(5):2049–2052PubMedGoogle Scholar
  51. Papanikolaou NC, Hatzidaki EG, Belivanis S, Tzanakakis GN, Tsatsakis AM (2005) Lead toxicity update. A brief review. Med Sci Monit 11(10):RA329–336PubMedGoogle Scholar
  52. Park JH, Lee DW, Park KS, Joung H (2014) Serum trace metal levels in Alzheimer’s disease and normal control groups. Am J Alzheimers Dis Other Demen 29(1):76–83PubMedGoogle Scholar
  53. Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL (1997) Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer diseased brain. Neurotoxicology 18(2):315–324PubMedGoogle Scholar
  54. Ricchelli F, Drago D, Filippi B, Tognon G, Zatta P (2005) Aluminum-triggered structural modifications and aggregation of beta-amyloids. Cell Mol Life Sci 62(15):1724–1733PubMedGoogle Scholar
  55. Roberts BR, Ryan TM, Bush AI, Masters CL, Duce JA (2012) The role of metallobiology and amyloid-β peptides in Alzheimer’s disease. J Neurochem 120(Suppl 1):149–166PubMedGoogle Scholar
  56. Roychaudhuri R, Yang M, Hoshi MM, Teplow DB (2009) Amyloid beta-protein assembly and Alzheimer disease. J Biol Chem 284(8):4749–4753PubMedGoogle Scholar
  57. Sanderson KL, Butler L, Ingram VM (1997) Aggregates of a beta-amyloid peptide are required to induce calcium currents in neuron-like human teratocarcinoma cells: relation to Alzheimer’s disease. Brain Res 744(1):7–14PubMedGoogle Scholar
  58. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359(6393):325–327PubMedGoogle Scholar
  59. Shafrir Y, Durell S, Arispe N, Guy HR (2010) Models of membrane-bound Alzheimer’s Abeta peptide assemblies. Proteins 78(16):3473–3487PubMedPubMedCentralGoogle Scholar
  60. Simmons MA, Schneider CR (1993) Amyloid beta peptides act directly on single neurons. Neurosci Lett 150(2):133–136PubMedGoogle Scholar
  61. Song JW, Choi BS (2013) Mercury induced the accumulation of Amyloid Beta (Aβ) in PC12 cells: the role of production and degradation of Aβ. Toxicol Res 29(4):235–240PubMedPubMedCentralGoogle Scholar
  62. Stipani V, Gallucci E, Micelli S, Picciarelli V, Benz R (2001) Channel formation by salmon and human calcitonin in black lipid membranes. Biophys J 81(6):3332–3338PubMedPubMedCentralGoogle Scholar
  63. Stoiber T, Bonacker D, Böhm KJ, Bolt HM, Thier R, Degen GH, Unger E (2004) Disturbed microtubule function and induction of micronuclei by chelate complexes of mercury(II). Mutat Res 563(2):97–106PubMedGoogle Scholar
  64. Sun L, Zhou XL, Yi HP, Jiang SJ, Yuan H (2014) Lead-induced morphological changes and amyloid precursor protein accumulation in adult rat hippocampus. Biotech Histochem 89(7):513–517PubMedGoogle Scholar
  65. Suresh C, Johnson J, Mohan R, Chetty CS (2012) Synergistic effects of amyloid peptides and lead on human neuroblastoma cells. Cell Mol Biol Lett 17(3):408–421PubMedPubMedCentralGoogle Scholar
  66. Tabner BJ, Turnbull S, El-Agnaf OM, Allsop D (2002) Formation of hydrogen peroxide and hydroxyl radicals from A(beta) and alpha-synuclein as a possible mechanism of cell death in Alzheimer’s disease and Parkinson’s disease. Free Radic Biol Med 32(11):1076–1083PubMedGoogle Scholar
  67. Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS (2009) RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci USA 106(47):20021–20026PubMedGoogle Scholar
  68. Tamás MJ, Sharma SK, Ibstedt S, Jacobson T, Christen P (2014) Heavy metals and metalloids as a cause for protein misfolding and aggregation. Biomolecules 4(1):252–267PubMedPubMedCentralGoogle Scholar
  69. Tien TH (1974) Bilayer lipid membrane: theory and practice. Marcel Dekker, New YorkGoogle Scholar
  70. Tien T, Mountz J, Martinosi A (1977) Protein-lipid interaction in bilayer lipid membranes (BLM). In: The enzyme of biological membranes, vol 1. Plenum, NY, pp 139–170Google Scholar
  71. Tong S, von Schirnding YE, Prapamontol T (2000) Environmental lead exposure: a public health problem of global dimensions. Bull World Health Organ 78(9):1068–1077PubMedPubMedCentralGoogle Scholar
  72. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539PubMedGoogle Scholar
  73. Weiner H, Frenkel D (2006) Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 6(5):404–416PubMedGoogle Scholar
  74. Wong PT, Schauerte JA, Wisser KC, Ding H, Lee EL, Steel DG, Gafni A (2009) Amyloid-beta membrane binding and permeabilization are distinct processes influenced separately by membrane charge and fluidity. J Mol Biol 386(1):81–96PubMedGoogle Scholar
  75. Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH (2008) Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 28(1):3–9PubMedPubMedCentralGoogle Scholar
  76. Yang T, Li S, Xu H, Walsh DM, Selkoe DJ (2017) Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J Neurosci 37(1):152–163PubMedPubMedCentralGoogle Scholar
  77. Yano K, Hirosawa N, Sakamoto Y, Katayama H, Moriguchi T (2003) Aggregations of amyloid beta-proteins in the presence of metal ions. Toxicol Lett 144(Supplement 1):s134Google Scholar

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© European Biophysical Societies' Association 2019

Authors and Affiliations

  1. 1.Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of Bari “Aldo Moro”BariItaly
  2. 2.Department of ChemistryUniversity of Bari “Aldo Moro”BariItaly

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