Skip to main content

Advertisement

SpringerLink
Log in

Trace metal contamination initiates the apparent auto-aggregation, amyloidosis, and oligomerization of Alzheimer’s Aβ peptides

  • Original Article
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

Nucleation-dependent protein aggregation (“seeding”) and amyloid fibril-free formation of soluble SDS-resistant oligomers (“oligomerization”) by hydrophobic interaction is an in vitro model thought to propagate β-amyloid (Aβ) deposition, accumulation, and incur neurotoxicity and synaptotoxicity in Alzheimer’s disease (AD), and other amyloid-associated neurodegenerative diseases. However, Aβ is a high-affinity metalloprotein that aggregates in the presence of biometals (zinc, copper, and iron), and neocortical Aβ deposition is abolished by genetic ablation of synaptic zinc in transgenic mice. We now present in vitro evidence that trace (≤0.8 µM) levels of zinc, copper, and iron, present as common contaminants of laboratory buffers and culture media, are the actual initiators of the classic Aβ1–42-mediated seeding process and Aβ oligomerization. Replicating the experimental conditions of earlier workers, we found that the in vitro precipitation and amyloidosis of Aβ1–40 (20 µM) initiated by Aβ1–42 (2 µM) were abolished by chelation of trace metal contaminants. Further, metal chelation attenuated formation of soluble Aβ oligomers from a cell-free culture medium. These data suggest that protein self-assembly and oligomerization are not spontaneous in this system as previously thought, and that there may be an obligatory role for metal ions in initiating Aβ amyloidosis and oligomerization.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A, B
Fig. 2A, B
Fig. 3A, B
Fig. 4

Similar content being viewed by others

Abbreviations

Aβ:

β-amyloid

AD:

Alzheimer’s disease

CR:

Congo Red

DMEM:

Dulbecco’s modified Eagle’s medium

DTPA:

diethylenetriaminepentaacetic acid

ICP-MS:

ion coupled plasma-mass spectroscopy

SDS-PAGE:

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

Th-T:

thioflavin-T

References

  1. Glenner GG, Wong CW (1984) Biochem Biophys Res Commun 120:885–890

    CAS  PubMed  Google Scholar 

  2. Vigo-Pelfrey C, Lee D, Keim P, Lieberburg I, Schenk DB (1993) J Neurochem 61:1965–1968

    CAS  PubMed  Google Scholar 

  3. Prelli F, Casta E, Glenner GG, Frangione B (1988) J Neurochem 51:648–651

    CAS  PubMed  Google Scholar 

  4. Suzuki A, Takashima S, Mizuguchi M, Kato M, Kunishita T, Tabira T (1994) Tohoku J Exp Med 174:181–187

    CAS  Google Scholar 

  5. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Nat Med 2:864–870

    Article  CAS  PubMed  Google Scholar 

  6. Hilbich C, Kisters-Woike B, Reed J, Masters CL, Beyreuther K (1991) J Mol Biol 218:149–163

    CAS  PubMed  Google Scholar 

  7. Hilbich C, Kisters-Woike B, Reed J, Masters CL, Beyreuther K (1992) J Mol Biol 228:460–473

    CAS  PubMed  Google Scholar 

  8. Barrow CJ, Zagorski MG (1991) Science 253:179–182

    CAS  PubMed  Google Scholar 

  9. Barrow CJ, Yasuda A, Kenny PT, Zagorski MG (1992) J Mol Biol 225:1075–1093

    CAS  PubMed  Google Scholar 

  10. Jarrett JT, Lansbury PT Jr (1993) Cell 73:1055–1058

    Article  CAS  PubMed  Google Scholar 

  11. Jarrett JT, Berger EP, Lansbury PT Jr (1993) Biochemistry 32:4693–4697

    CAS  PubMed  Google Scholar 

  12. Come JH, Fraser PE, Lansbury PT Jr (1993) Proc Natl Acad Sci USA 90:5959–5963

    CAS  PubMed  Google Scholar 

  13. Bush AI, Pettingell WH Jr, Paradis MD, Tanzi RE (1994) J Biol Chem 269:12152–12158

    CAS  PubMed  Google Scholar 

  14. Bush AI, Pettingell WH, Multhaup G, Paradis MD, Vonsattel J-P, Gusella JF, Beyreuther K, Masters CL, Tanzi RE (1994) Science 265:1464–1467

    CAS  PubMed  Google Scholar 

  15. Garzon-Rodriguez W, Sepulveda-Becerra M, Milton S, Glabe CG (1997) J Biol Chem 272:21037–21044

    Article  CAS  PubMed  Google Scholar 

  16. Huang X, Atwood CS, Moir RD, Hartshorn MA, Vonsattel JP, Tanzi RE, Bush AI (1997) J Biol Chem 272:26464–26470

    Article  CAS  PubMed  Google Scholar 

  17. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI (1998) J Biol Chem 273:12817–12826

    Article  CAS  PubMed  Google Scholar 

  18. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) J Neurol Sci 158:47–52

    Article  CAS  PubMed  Google Scholar 

  19. Lee JY, Mook-Jung I, Koh JY (1999) J Neurosci 19:RC10

    CAS  PubMed  Google Scholar 

  20. Suh SW, Jensen KB, Jensen MS, Silva DS, Kesslak PJ, Danscher G, Frederickson CJ (2000) Brain Res 852:274–278

    Article  CAS  PubMed  Google Scholar 

  21. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY (2002) Proc Natl Acad Sci USA 99:7705–7710

    Article  CAS  PubMed  Google Scholar 

  22. Friedlich AL, Lee JY, van Groen T, Cherny RA, Volitakis I, Cole TB, Palmiter RD, Koh JY, Bush AI (2004) J Neurosci 24:3453–3459

    Article  CAS  PubMed  Google Scholar 

  23. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Nature 383:710–713

    Article  CAS  PubMed  Google Scholar 

  24. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Proc Natl Acad Sci USA 95:6448–6453

    Article  CAS  PubMed  Google Scholar 

  25. Roher AE, Chaney MO, Kuo YM, Webster SD, Stine WB, Haverkamp LJ, Woods AS, Cotter RJ, Tuohy JM, Krafft GA, Bonnell BS, Emmerling MR (1996) J Biol Chem 271:20631–20635

    Article  CAS  PubMed  Google Scholar 

  26. Nakabayashi J, Yoshimura M, Morishima-Kawashima M, Funato H, Miyakawa T, Yamazaki T, Ihara Y (1998) J Neuropathol Exp Neurol 57:343–352

    CAS  PubMed  Google Scholar 

  27. Enya M, Morishima-Kawashima M, Yoshimura M, Shinkai Y, Kusui K, Khan K, Games D, Schenk D, Sugihara S, Yamaguchi H, Ihara Y (1999) Am J Pathol 154:271–279

    CAS  PubMed  Google Scholar 

  28. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Ann Neurol 46:860–866

    Google Scholar 

  29. Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ (2000) Biochemistry 39:10831–10839

    Article  CAS  PubMed  Google Scholar 

  30. Podlisny MB, Ostaszewski BL, Squazzo SL, Koo EH, Rydell RE, Teplow DB, Selkoe DJ (1995) J Biol Chem 270:9564–9570

    Article  CAS  PubMed  Google Scholar 

  31. Podlisny MB, Walsh DM, Amarante P, Ostaszewski BL, Stimson ER, Maggio JE, Teplow DB, Selkoe DJ (1998) Biochemistry 37:3602–3611

    Article  CAS  PubMed  Google Scholar 

  32. Xia W, Zhang J, Kholodenko D, Citron M, Podlisny MB, Teplow DB, Haass C, Seubert P, Koo EH, Selkoe DJ (1997) J Biol Chem 272:7977–7982

    Article  CAS  PubMed  Google Scholar 

  33. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Nature 416:535–539

    Article  CAS  PubMed  Google Scholar 

  34. Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL (2003) Proc Natl Acad Sci USA 100:10417–10422

    Article  CAS  PubMed  Google Scholar 

  35. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Science 300:486–489

    Article  CAS  PubMed  Google Scholar 

  36. Atwood CS, Perry G, Zeng H, Kato Y, Jones WD, Ling KQ, Huang X, Moir RD, Wang D, Sayre LM, Smith MA, Chen SG, Bush AI (2004) Biochemistry 43:560–568

    Article  CAS  PubMed  Google Scholar 

  37. Huang X, Olmez I, Aras NK, Gordon GE (1994) Atmos Environ 28:1385–1391

    Article  Google Scholar 

  38. Wood SJ, Maleeff B, Hart T, Wetzel R (1996) J Mol Biol 256:870–877

    Article  CAS  PubMed  Google Scholar 

  39. Klunk WE, Pettegrew JW, Abraham DJ (1989) J Histochem Cytochem 37:1293–1297

    CAS  PubMed  Google Scholar 

  40. Bush AI, Moir RD, Rosenkranz KM, Tanzi RE (1995) Science 268:1921–1923

    CAS  Google Scholar 

  41. LeVine HD (1993) Protein Sci 2:404–410

    CAS  PubMed  Google Scholar 

  42. Huang X, Atwood CS, Goldstein LE, Hartshorn MA, Saunders AJ, Moir RD, Tanzi RE, Bush AI (1999) In: Iqbal K, Swaab DF, Winblad B, Wisniewski HM (eds) Alzheimer’s disease and related disorders: etiology, pathogenesis and therapeutics. Wiley, Chichester, UK, pp 383–390

  43. Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scrapa SC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI (1999) Biochemistry 38:7609–7616

    Article  CAS  PubMed  Google Scholar 

  44. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ (2001) J Biol Chem 276: 20466–20473

    Article  CAS  PubMed  Google Scholar 

  45. Sengupta P, Garai K, Sahoo B, Shi Y, Callaway DJ, Maiti S (2003) Biochemistry 42:10506–10513

    Article  CAS  PubMed  Google Scholar 

  46. Loeffler DA, LeWitt PA, Juneau PL, Sima AA, Nguyen HU, DeMaggio AJ, Brickman CM, Brewer GJ, Dick RD, Troyer MD, Kanaley L (1996) Brain Res 738:265–274

    Article  CAS  PubMed  Google Scholar 

  47. Van Gool D, De Strooper B, Van Leuven F, Triau E, Dom R (1993) Neurobiol Aging 14:233–237

    Article  PubMed  Google Scholar 

  48. Grundke-Iqbal I, Fleming J, Tung YC, Lassmann H, Iqbal K, Joshi JG (1990) Acta Neuropathol (Berlin) 81:105–110

    Google Scholar 

  49. Loeffler DA, Connor JR, Juneau PL, Snyder BS, Kanaley L, DeMaggio AJ, Nguyen H, Brickman CM, LeWitt PA (1995) J Neurochem 65:710–724

    CAS  PubMed  Google Scholar 

  50. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Neuron 30:665–676

    Article  CAS  PubMed  Google Scholar 

  51. Regland B, Lehmann W, Abedini I, Blennow K, Jonsson M, Karlsson I, Sjogren M, Wallin A, Xilinas M, Gottfries CG (2001) Dement Geriatr Cogn Disord 12:408–414

    Article  CAS  PubMed  Google Scholar 

  52. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL (2003) Arch Neurol 60:1685–1691

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

X.H. was supported by a NRSA award (5F32AG05782) from the NIH, and is a recipient of an NIH Career Development grant (5K01MH02001) and an AFAR grant. A.I.B. was supported by funds from the NIA (5R01AG12685), the American Health Assistance Foundation, the Alzheimer Association, and the Neuroscience Research and Education Foundation. R.E.T. is an Ellison Medical Foundation Senior Scholar.

Author information

Author notes

  1. Craig S. Atwood

    Present address: Department of Medicine, University of Wisconsin, Madison, WI , 53705, USA

Authors and Affiliations

  1. Department of Psychiatry, and Laboratory for Oxidation Biology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA , 02114, USA

    Xudong Huang, Craig S. Atwood, Mariana A. Hartshorn & Ashley I. Bush

  2. Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA , 02114, USA

    Robert D. Moir & Rudolph E. Tanzi

Authors
  1. Xudong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig S. Atwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert D. Moir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariana A. Hartshorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rudolph E. Tanzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ashley I. Bush
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xudong Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, X., Atwood, C.S., Moir, R.D. et al. Trace metal contamination initiates the apparent auto-aggregation, amyloidosis, and oligomerization of Alzheimer’s Aβ peptides. J Biol Inorg Chem 9, 954–960 (2004). https://doi.org/10.1007/s00775-004-0602-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-004-0602-8

Keywords

Search

Navigation