Monatshefte für Chemie - Chemical Monthly

, Volume 142, Issue 4, pp 421–430 | Cite as

Beta-amyloid toxicity increases with hydrophobicity in the presence of metal ions

  • Alberto Granzotto
  • Silvia Bolognin
  • Janez Scancar
  • Radmila Milacic
  • Paolo ZattaEmail author
Original Paper


Alzheimer’s disease is a multifactorial neurodegenerative disorder characterized by the pathological brain deposition of neurofibrillary tangles and senile plaques. The latter consist mainly of insoluble β-amyloid (Aβ) fibril deposition. Aβ aggregation and deposition can be increased by several factors, including metal ions. In this study we investigated the role played by metal ions in affecting Aβ oligomerization in the presence and in the absence of its hydrophobic fragment Aβ17–28. This was done not as a physiological investigation, but as a paradigmatic study to confirm the key role of Aβ superficial hydrophobicity as a relevant aggravating factor that contributes to the toxicity of Aβ and Aβ–metal complexes. The structural conformations of Aβ–metal complexes were monitored through fluorescence and turbidity measurements as well as transmission electron microscopy. Results reported herein indicate that various metals differentially influence Aβ conformation, with aluminum being the only metal ion for which we are able to determine a dramatic enhancement of peptide oligomer formation with a consequent toxic effect. This scenario was further enhanced by the presence of Aβ17–28, which resulted in a marked toxicity in a neuroblastoma cell culture as a consequence of the enhancement of the hydrophobicity of the amyloid and amyloid–metal complexes.

Graphical abstract


Amyloid-beta Aluminum Alzheimer’s disease Metal ions Hydrophobicity 



This work was supported by PRIN 2007.


  1. 1.
    Iqbal K, Liu F, Gong CX, Alonso AD, Grundke-Iqbal I (2009) Acta Neuropathol 118:53CrossRefGoogle Scholar
  2. 2.
    Ono K, Condron MM, Teplow DB (2009) Proc Natl Acad Sci USA 106:14745CrossRefGoogle Scholar
  3. 3.
    Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C (2009) N Engl J Med 360:2302CrossRefGoogle Scholar
  4. 4.
    Nygaard HB, Strittmatter SM (2009) AMA Arch Neurol 66:1325CrossRefGoogle Scholar
  5. 5.
    Zatta P, Drago D, Bolognin S, Sensi SL (2009) Trends Pharmacol Sci 30:346Google Scholar
  6. 6.
    Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) J Neurol Sci 158:47CrossRefGoogle Scholar
  7. 7.
    Miller LM, Wang Q, Telivala TP, Smith RJ, Lanzirotti A, Miklossy J (2006) J Struct Biol 155:30CrossRefGoogle Scholar
  8. 8.
    Leskovjan AC, Lanzirotti A, Miller LM (2009) Neuroimage 47:1215CrossRefGoogle Scholar
  9. 9.
    Zbilut JP, Webber CL, Colosimo A, Giuliani A (2000) Protein Eng 13:99CrossRefGoogle Scholar
  10. 10.
    Kim W, Hecht MH (2006) Proc Natl Acad Sci USA 103:15824CrossRefGoogle Scholar
  11. 11.
    Dahlgren KN, Manelli AM, Stine WB, Baker LK, Krafft GA, LaDu MJ (2002) J Biol Chem 277:32046CrossRefGoogle Scholar
  12. 12.
    Drago D, Folin M, Baiguera S, Tognon G, Ricchelli F, Zatta P (2007) J Alzheimers Dis 11:33Google Scholar
  13. 13.
    Shearman MS, Hawtin SR, Tailor VJ (1995) J Neurochem 65:218CrossRefGoogle Scholar
  14. 14.
    Maezawa I, Hong HS, Liu R, Wu CY, Cheng RH, Kung MP, Kung HF, Lam KS, Oddo S, LaFerla FM, Jin LW (2008) J Neurochem 104:457Google Scholar
  15. 15.
    Ferreira ST, Vieira MNN, De Felice FG (2007) IUBMB Life 59:332CrossRefGoogle Scholar
  16. 16.
    Naiki H, Gejyo F, Nakakuki K (1997) Biochemistry 36:6243CrossRefGoogle Scholar
  17. 17.
    Uversky VN, Winter S, Lober G (1996) Biophys Chem 60:79CrossRefGoogle Scholar
  18. 18.
    Drago D, Bolognin S, Zatta P (2008) Curr Alzheimer Res 5:500CrossRefGoogle Scholar
  19. 19.
    Friedman R, Pellarin R, Caflisch A (2009) J Mol Biol 387:407CrossRefGoogle Scholar
  20. 20.
    Suwalsky M, Bolognin S, Zatta P (2009) J Alzheimers Dis 17:81Google Scholar
  21. 21.
    Yankner BA, Lu T (2009) J Biol Chem 284:4754Google Scholar
  22. 22.
    Kopito RR, Ron D (2000) Nat Cell Biol 2:E207CrossRefGoogle Scholar
  23. 23.
    Drago D, Bettella M, Bolognin S, Cendron L, Scancar J, Milacic R, Ricchelli F, Casini A, Messori L, Tognon G, Zatta P (2008) Int J Biochem Cell B 40:731CrossRefGoogle Scholar
  24. 24.
    Millucci L, Ghezzi L, Bernardini G, Santucci A (2010) Curr Protein Pep Sc 11:457Google Scholar
  25. 25.
    Atamna H (2009) J Bioenerg Biomembr 41:457CrossRefGoogle Scholar
  26. 26.
    Tjernberg LO, Callaway DJE, Tjernberg A, Hahne S, Lilliehook C, Terenius L, Thyberg J, Nordstedt C (1999) J Biol Chem 274:12619CrossRefGoogle Scholar
  27. 27.
    Melquiond A, Dong X, Mousseau N, Derreumaux P (2008) Curr Alzheimer Res 5:244CrossRefGoogle Scholar
  28. 28.
    Levine H (1993) Protein Sci 2:404CrossRefGoogle Scholar
  29. 29.
    Xue WF, Hellewell AL, Gosal WS, Homans SW, Hewitt EW, Radford SE (2009) J Biol Chem 284:34272CrossRefGoogle Scholar
  30. 30.
    Zhang A, Qi W, Good TA, Fernandez EJ (2009) Biophys J 96:1091CrossRefGoogle Scholar
  31. 31.
    Shah SB, Nolan R, Davis E, Stokin GB, Niesman I, Canto I, Glabe C, Goldstein LSB (2009) Neurobiol Dis 36:11CrossRefGoogle Scholar
  32. 32.
    Deshpande A, Mina E, Glabe C, Busciglio J (2006) J Neurosci 26:6011CrossRefGoogle Scholar
  33. 33.
    Behl C, Davis JB, Lesley R, Schubert D (1994) Cell 77:817CrossRefGoogle Scholar
  34. 34.
    Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan JY (2000) Nature 403:98CrossRefGoogle Scholar
  35. 35.
    Kremer JJ, Pallitto MM, Sklansky DJ, Murphy RM (2000) Biochemistry 39:10309CrossRefGoogle Scholar
  36. 36.
    Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT (2002) Nature 418:291CrossRefGoogle Scholar
  37. 37.
    Eckert GP, Wood WG, Muller WE (2005) Subcell Biochem 38:319CrossRefGoogle Scholar
  38. 38.
    Miller Y, Ma B, Nussinov R (2010) Chem Rev 110:4820CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Alberto Granzotto
    • 1
  • Silvia Bolognin
    • 1
  • Janez Scancar
    • 2
  • Radmila Milacic
    • 2
  • Paolo Zatta
    • 1
    Email author
  1. 1.Department of Biology, Padua “Metalloproteins” Unit, CNR-Institute for Biomedical TechnologiesUniversity of PaduaPaduaItaly
  2. 2.Department of Environmental SciencesJosef Stefan InstituteLjubljanaSlovenia

Personalised recommendations