Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Feb 20;93(4):1710–1715. doi: 10.1073/pnas.93.4.1710

Zn2+ interaction with Alzheimer amyloid beta protein calcium channels.

N Arispe 1, H B Pollard 1, E Rojas 1
PMCID: PMC40007  PMID: 8643694

Abstract

The Alzheimer disease 40-residue amyloid beta protein (AbetaP[1-40]) forms cation-selective channels across acidic phospholipid bilayer membranes with spontaneous transitions over a wide range of conductances ranging from 40 to 4000 pS. Zn2+ has been reported to bind to AbetaP[1-40] with high affinity, and it has been implicated in the formation of amyloid plaques. We now report the functional consequences of such Zn2+ binding for the AbetaP[1-40] channel. Provided the AbetaP[1-40] channel is expressed in the low conductance (<400 pS) mode, Zn2+ blocks the open channel in a dose- dependent manner. For AbetaP[1-40] channels in the giant conductance mode (>400 pS), Zn2+ doses in the millimolar range were required to exert substantial blockade. The Zn2+ chelator o-phenanthroline reverses the blockade. We also found that Zn2+ modulates AbetaP[1-40] channel gating and conductance only from one side of the channel. These data are consistent with predictions of our recent molecular modeling studies on AbetaP[1-40] channels indicating asymmetric Zn(2+)-AbetaP[1-40] interactions at the entrance to the pore.

Full text

PDF
1710

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arispe N., Pollard H. B., Rojas E. Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10573–10577. doi: 10.1073/pnas.90.22.10573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arispe N., Pollard H. B., Rojas E. The ability of amyloid beta-protein [A beta P (1-40)] to form Ca2+ channels provides a mechanism for neuronal death in Alzheimer's disease. Ann N Y Acad Sci. 1994 Dec 15;747:256–266. doi: 10.1111/j.1749-6632.1994.tb44414.x. [DOI] [PubMed] [Google Scholar]
  3. Arispe N., Pollard H. B., Rojas E. beta-Amyloid Ca(2+)-channel hypothesis for neuronal death in Alzheimer disease. Mol Cell Biochem. 1994 Nov 23;140(2):119–125. doi: 10.1007/BF00926750. [DOI] [PubMed] [Google Scholar]
  4. Arispe N., Rojas E., Pollard H. B. Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):567–571. doi: 10.1073/pnas.90.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Becker A. B., Roth R. A. Identification of glutamate-169 as the third zinc-binding residue in proteinase III, a member of the family of insulin-degrading enzymes. Biochem J. 1993 May 15;292(Pt 1):137–142. doi: 10.1042/bj2920137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brzović P. S., Choi W. E., Borchardt D., Kaarsholm N. C., Dunn M. F. Structural asymmetry and half-site reactivity in the T to R allosteric transition of the insulin hexamer. Biochemistry. 1994 Nov 8;33(44):13057–13069. doi: 10.1021/bi00248a015. [DOI] [PubMed] [Google Scholar]
  7. Bush A. I., Multhaup G., Moir R. D., Williamson T. G., Small D. H., Rumble B., Pollwein P., Beyreuther K., Masters C. L. A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer's disease. J Biol Chem. 1993 Aug 5;268(22):16109–16112. [PubMed] [Google Scholar]
  8. Bush A. I., Pettingell W. H., Jr, Paradis M. D., Tanzi R. E. Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem. 1994 Apr 22;269(16):12152–12158. [PubMed] [Google Scholar]
  9. Ciszak E., Smith G. D. Crystallographic evidence for dual coordination around zinc in the T3R3 human insulin hexamer. Biochemistry. 1994 Feb 15;33(6):1512–1517. doi: 10.1021/bi00172a030. [DOI] [PubMed] [Google Scholar]
  10. Durell S. R., Guy H. R., Arispe N., Rojas E., Pollard H. B. Theoretical models of the ion channel structure of amyloid beta-protein. Biophys J. 1994 Dec;67(6):2137–2145. doi: 10.1016/S0006-3495(94)80717-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frederickson C. J. Neurobiology of zinc and zinc-containing neurons. Int Rev Neurobiol. 1989;31:145–238. doi: 10.1016/s0074-7742(08)60279-2. [DOI] [PubMed] [Google Scholar]
  12. Gehm B. D., Kuo W. L., Perlman R. K., Rosner M. R. Mutations in a zinc-binding domain of human insulin-degrading enzyme eliminate catalytic activity but not insulin binding. J Biol Chem. 1993 Apr 15;268(11):7943–7948. [PubMed] [Google Scholar]
  13. Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., Gajdusek D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987 Feb 20;235(4791):877–880. doi: 10.1126/science.3810169. [DOI] [PubMed] [Google Scholar]
  14. Gross L., Dunn M. F. Spectroscopic evidence for an intermediate in the T6 to R6 allosteric transition of the Co(II)-substituted insulin hexamer. Biochemistry. 1992 Feb 11;31(5):1295–1301. doi: 10.1021/bi00120a004. [DOI] [PubMed] [Google Scholar]
  15. Hardy J. A., Higgins G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992 Apr 10;256(5054):184–185. doi: 10.1126/science.1566067. [DOI] [PubMed] [Google Scholar]
  16. Hyman B. T., Van Hoesen G. W., Kromer L. J., Damasio A. R. Perforant pathway changes and the memory impairment of Alzheimer's disease. Ann Neurol. 1986 Oct;20(4):472–481. doi: 10.1002/ana.410200406. [DOI] [PubMed] [Google Scholar]
  17. Jacoby E., Krüger P., Karatas Y., Wollmer A. Distinction of structural reorganisation and ligand binding in the T<==>R transition of insulin on the basis of allosteric models. Biol Chem Hoppe Seyler. 1993 Sep;374(9):877–885. doi: 10.1515/bchm3.1993.374.7-12.877. [DOI] [PubMed] [Google Scholar]
  18. Joachim C. L., Duffy L. K., Morris J. H., Selkoe D. J. Protein chemical and immunocytochemical studies of meningovascular beta-amyloid protein in Alzheimer's disease and normal aging. Brain Res. 1988 Nov 22;474(1):100–111. doi: 10.1016/0006-8993(88)90673-7. [DOI] [PubMed] [Google Scholar]
  19. Kawahara M., Muramoto K., Kobayashi K., Mori H., Kuroda Y. Aluminum promotes the aggregation of Alzheimer's amyloid beta-protein in vitro. Biochem Biophys Res Commun. 1994 Jan 28;198(2):531–535. doi: 10.1006/bbrc.1994.1078. [DOI] [PubMed] [Google Scholar]
  20. Kowall N. W., McKee A. C., Yankner B. A., Beal M. F. In vivo neurotoxicity of beta-amyloid [beta(1-40)] and the beta(25-35) fragment. Neurobiol Aging. 1992 Sep-Oct;13(5):537–542. doi: 10.1016/0197-4580(92)90053-z. [DOI] [PubMed] [Google Scholar]
  21. Kuroda Y., Kawahara M. Aggregation of amyloid beta-protein and its neurotoxicity: enhancement by aluminum and other metals. Tohoku J Exp Med. 1994 Nov;174(3):263–268. doi: 10.1620/tjem.174.263. [DOI] [PubMed] [Google Scholar]
  22. Malouf A. T. Effect of beta amyloid peptides on neurons in hippocampal slice cultures. Neurobiol Aging. 1992 Sep-Oct;13(5):543–551. doi: 10.1016/0197-4580(92)90054-2. [DOI] [PubMed] [Google Scholar]
  23. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245–4249. doi: 10.1073/pnas.82.12.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McLachlan D. R., Fraser P. E., Dalton A. J. Aluminium and the pathogenesis of Alzheimer's disease: a summary of evidence. Ciba Found Symp. 1992;169:87–108. doi: 10.1002/9780470514306.ch6. [DOI] [PubMed] [Google Scholar]
  25. Neve R. L., Dawes L. R., Yankner B. A., Benowitz L. I., Rodriguez W., Higgins G. A. Genetics and biology of the Alzheimer amyloid precursor. Prog Brain Res. 1990;86:257–267. doi: 10.1016/s0079-6123(08)63182-9. [DOI] [PubMed] [Google Scholar]
  26. Perlman R. K., Rosner M. R. Identification of zinc ligands of the insulin-degrading enzyme. J Biol Chem. 1994 Dec 30;269(52):33140–33145. [PubMed] [Google Scholar]
  27. Pollard J. R., Arispe N., Rojas E., Pollard H. B. A geometric sequence that accurately describes allowed multiple conductance levels of ion channels: the "three-halves (3/2) rule". Biophys J. 1994 Aug;67(2):647–655. doi: 10.1016/S0006-3495(94)80525-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Roth M., Tomlinson B. E., Blessed G. Correlation between scores for dementia and counts of 'senile plaques' in cerebral grey matter of elderly subjects. Nature. 1966 Jan 1;209(5018):109–110. doi: 10.1038/209109a0. [DOI] [PubMed] [Google Scholar]
  29. Selkoe D. J. The molecular pathology of Alzheimer's disease. Neuron. 1991 Apr;6(4):487–498. doi: 10.1016/0896-6273(91)90052-2. [DOI] [PubMed] [Google Scholar]
  30. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A., St George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., Neve R. L. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880–884. doi: 10.1126/science.2949367. [DOI] [PubMed] [Google Scholar]
  31. Yankner B. A. Commentary and perspective on studies of beta amyloid neurotoxicity. Neurobiol Aging. 1992 Sep-Oct;13(5):615–616. doi: 10.1016/0197-4580(92)90067-8. [DOI] [PubMed] [Google Scholar]
  32. Yankner B. A., Duffy L. K., Kirschner D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990 Oct 12;250(4978):279–282. doi: 10.1126/science.2218531. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES