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. 1994 Sep;102(Suppl 3):207–213. doi: 10.1289/ehp.94102s3207

Iron and aluminum homeostasis in neural disorders.

J G Joshi 1, M Dhar 1, M Clauberg 1, V Chauthaiwale 1
PMCID: PMC1567377  PMID: 7843099

Abstract

The brain is the most compartmentalized organ. It is also highly aerobic. Because nerve cells grow but do not regenerate, the brain is the organ best suited for the accumulation of metabolic errors colocalized in specific areas of the brain over an extended period. Alzheimer's disease (AD) is primarily a neurological disorder of the elderly. It is suggested that this disorder results from the accumulation of such errors, and that AD onset aluminum and iron contribute to but do not necessarily initiate the onset of the disease. In vitro and in vivo evidence summarized here suggests that this is effected by interfering in the utilization of glucose and glucose-6-phosphate, and sequestration of iron by ferritin. beta-amyloid precusor proteins (beta-APPs) are normal components of the human brain and some other tissues. Proteolysis of these, presumably by serine proteases, generates a 39 to 42 amino acid long peptide, the alpha-amyloid (beta-AP). In AD brains, beta-AP aggregates into plaque, the hallmark of AD brains. Some of the alpha-APPs also contain a 56 amino acid long segment which inhibits serine proteases. We show that in vitro, at pH 6.5, aluminum activates beta-chymotrypsin 2-fold and makes it dramatically resistant to protease inhibitors such as bovine pancreatic trypsin inhibitor (bPTI) or its mimic present in the beta-amyloid precursor proteins (beta-APPs). Iron and oxygen are reported to favor cross-linking of beta-AP in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Aisen P., Listowsky I. Iron transport and storage proteins. Annu Rev Biochem. 1980;49:357–393. doi: 10.1146/annurev.bi.49.070180.002041. [DOI] [PubMed] [Google Scholar]
  2. Allen D. D., Yokel R. A. Dissimilar aluminum and gallium permeation of the blood-brain barrier demonstrated by in vivo microdialysis. J Neurochem. 1992 Mar;58(3):903–908. doi: 10.1111/j.1471-4159.1992.tb09342.x. [DOI] [PubMed] [Google Scholar]
  3. Barrow C. J., Zagorski M. G. Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition. Science. 1991 Jul 12;253(5016):179–182. doi: 10.1126/science.1853202. [DOI] [PubMed] [Google Scholar]
  4. Bélanger C. What do you know about Joseph Babinski? Can J Neurol Sci. 1989 Feb;16(1):1–7. [PubMed] [Google Scholar]
  5. Candy J. M., Oakley A. E., Klinowski J., Carpenter T. A., Perry R. H., Atack J. R., Perry E. K., Blessed G., Fairbairn A., Edwardson J. A. Aluminosilicates and senile plaque formation in Alzheimer's disease. Lancet. 1986 Feb 15;1(8477):354–357. doi: 10.1016/s0140-6736(86)92319-6. [DOI] [PubMed] [Google Scholar]
  6. Cho S. W., Joshi J. G. Characterization of glucose-6-phosphate dehydrogenase isozymes from human and pig brain. Neuroscience. 1990;38(3):819–828. doi: 10.1016/0306-4522(90)90074-e. [DOI] [PubMed] [Google Scholar]
  7. Cho S., Joshi J. G. Effect of long-term feeding of aluminium chloride on hexokinase and glucose-6-phosphate dehydrogenase in the brain. Toxicology. 1988 Jan;48(1):61–69. doi: 10.1016/0300-483x(88)90059-5. [DOI] [PubMed] [Google Scholar]
  8. Clauberg M., Joshi J. G. Regulation of serine protease activity by aluminum: implications for Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1009–1012. doi: 10.1073/pnas.90.3.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cochran M., Chawtur V. Interaction of horse-spleen ferritin with aluminium citrate. Clin Chim Acta. 1988 Nov;178(1):79–84. doi: 10.1016/0009-8981(88)90271-9. [DOI] [PubMed] [Google Scholar]
  10. Cochran M., Coates J., Neoh S. The competitive equilibrium between aluminium and ferric ions for the binding sites of transferrin. FEBS Lett. 1984 Oct 15;176(1):129–132. doi: 10.1016/0014-5793(84)80926-6. [DOI] [PubMed] [Google Scholar]
  11. Connor J. R., Menzies S. L., St Martin S. M., Mufson E. J. A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains. J Neurosci Res. 1992 Jan;31(1):75–83. doi: 10.1002/jnr.490310111. [DOI] [PubMed] [Google Scholar]
  12. Crapper McLachlan D. R., Dalton A. J., Kruck T. P., Bell M. Y., Smith W. L., Kalow W., Andrews D. F. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet. 1991 Jun 1;337(8753):1304–1308. doi: 10.1016/0140-6736(91)92978-b. [DOI] [PubMed] [Google Scholar]
  13. Dedman D. J., Treffry A., Candy J. M., Taylor G. A., Morris C. M., Bloxham C. A., Perry R. H., Edwardson J. A., Harrison P. M. Iron and aluminium in relation to brain ferritin in normal individuals and Alzheimer's-disease and chronic renal-dialysis patients. Biochem J. 1992 Oct 15;287(Pt 2):509–514. doi: 10.1042/bj2870509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dhar M., Chauthaiwale V., Joshi J. G. Sequence of a cDNA encoding the ferritin H-chain from an 11-week-old human fetal brain. Gene. 1993 Apr 30;126(2):275–278. doi: 10.1016/0378-1119(93)90380-l. [DOI] [PubMed] [Google Scholar]
  15. Fleming J. T., Joshi J. G. Ferritin: the role of aluminum in ferritin function. Neurobiol Aging. 1991 Sep-Oct;12(5):413–418. doi: 10.1016/0197-4580(91)90066-s. [DOI] [PubMed] [Google Scholar]
  16. Fleming J., Joshi J. G. Ferritin: isolation of aluminum-ferritin complex from brain. Proc Natl Acad Sci U S A. 1987 Nov;84(22):7866–7870. doi: 10.1073/pnas.84.22.7866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fridovich I. Superoxide dismutases. An adaptation to a paramagnetic gas. J Biol Chem. 1989 May 15;264(14):7761–7764. [PubMed] [Google Scholar]
  18. Grundke-Iqbal I., Fleming J., Tung Y. C., Lassmann H., Iqbal K., Joshi J. G. Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia. Acta Neuropathol. 1990;81(2):105–110. doi: 10.1007/BF00334497. [DOI] [PubMed] [Google Scholar]
  19. Gutteridge J. M., Quinlan G. J., Clark I., Halliwell B. Aluminium salts accelerate peroxidation of membrane lipids stimulated by iron salts. Biochim Biophys Acta. 1985 Jul 31;835(3):441–447. doi: 10.1016/0005-2760(85)90113-4. [DOI] [PubMed] [Google Scholar]
  20. HALLGREN B., SOURANDER P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958 Oct;3(1):41–51. doi: 10.1111/j.1471-4159.1958.tb12607.x. [DOI] [PubMed] [Google Scholar]
  21. Harford J. B., Klausner R. D. Coordinate post-transcriptional regulation of ferritin and transferrin receptor expression: the role of regulated RNA-protein interaction. Enzyme. 1990;44(1-4):28–41. doi: 10.1159/000468745. [DOI] [PubMed] [Google Scholar]
  22. Hinman A. R., Orenstein W. A. Immunisation practice in developed countries. Lancet. 1990 Mar 24;335(8691):707–710. doi: 10.1016/0140-6736(90)90814-l. [DOI] [PubMed] [Google Scholar]
  23. Johnson G. V., Jope R. S. Aluminum impairs glucose utilization and cholinergic activity in rat brain in vitro. Toxicology. 1986 Jul;40(1):93–102. doi: 10.1016/0300-483x(86)90049-1. [DOI] [PubMed] [Google Scholar]
  24. Joshi J. G. Aluminum, a neurotoxin which affects diverse metabolic reactions. Biofactors. 1990 Jul;2(3):163–169. [PubMed] [Google Scholar]
  25. Joshi J. G., Clauberg M. Ferritin: an iron storage protein with diverse functions. Biofactors. 1988 Oct;1(3):207–212. [PubMed] [Google Scholar]
  26. Landsberg J. P., McDonald B., Watt F. Absence of aluminium in neuritic plaque cores in Alzheimer's disease. Nature. 1992 Nov 5;360(6399):65–68. doi: 10.1038/360065a0. [DOI] [PubMed] [Google Scholar]
  27. Marcus D. L., de Leon M. J., Goldman J., Logan J., Christman D. R., Wolf A. P., Fowler J. S., Hunter K., Tsai J., Pearson J. Altered glucose metabolism in microvessels from patients with Alzheimer's disease. Ann Neurol. 1989 Jul;26(1):91–94. doi: 10.1002/ana.410260114. [DOI] [PubMed] [Google Scholar]
  28. Markesbery W. R., Ehmann W. D., Hossain T. I., Alauddin M., Goodin D. T. Instrumental neutron activation analysis of brain aluminum in Alzheimer disease and aging. Ann Neurol. 1981 Dec;10(6):511–516. doi: 10.1002/ana.410100604. [DOI] [PubMed] [Google Scholar]
  29. Martin R. B. The chemistry of aluminum as related to biology and medicine. Clin Chem. 1986 Oct;32(10):1797–1806. [PubMed] [Google Scholar]
  30. Martyn C. N., Barker D. J., Osmond C., Harris E. C., Edwardson J. A., Lacey R. F. Geographical relation between Alzheimer's disease and aluminum in drinking water. Lancet. 1989 Jan 14;1(8629):59–62. [PubMed] [Google Scholar]
  31. Miller J. L., Hubbard C. M., Litman B. J., Macdonald T. L. Inhibition of transducin activation and guanosine triphosphatase activity by aluminum ion. J Biol Chem. 1989 Jan 5;264(1):243–250. [PubMed] [Google Scholar]
  32. Munekata K., Hossmann K. A. Effect of 5-minute ischemia on regional pH and energy state of the gerbil brain: relation to selective vulnerability of the hippocampus. Stroke. 1987 Mar-Apr;18(2):412–417. doi: 10.1161/01.str.18.2.412. [DOI] [PubMed] [Google Scholar]
  33. Ogush S., Lawson J. W., Dobson G. P., Veech R. L., Uyeda K. A new transient activator of phosphofructokinase during initiation of rapid glycolysis in brain. J Biol Chem. 1990 Jul 5;265(19):10943–10949. [PubMed] [Google Scholar]
  34. Paschen W., Djuricic B., Mies G., Schmidt-Kastner R., Linn F. Lactate and pH in the brain: association and dissociation in different pathophysiological states. J Neurochem. 1987 Jan;48(1):154–159. doi: 10.1111/j.1471-4159.1987.tb13140.x. [DOI] [PubMed] [Google Scholar]
  35. Perl D. P., Brody A. R. Alzheimer's disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science. 1980 Apr 18;208(4441):297–299. doi: 10.1126/science.7367858. [DOI] [PubMed] [Google Scholar]
  36. Schellenberg G. D., Bird T. D., Wijsman E. M., Orr H. T., Anderson L., Nemens E., White J. A., Bonnycastle L., Weber J. L., Alonso M. E. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science. 1992 Oct 23;258(5082):668–671. doi: 10.1126/science.1411576. [DOI] [PubMed] [Google Scholar]
  37. Selkoe D. J. Deciphering Alzheimer's disease: the amyloid precursor protein yields new clues. Science. 1990 Jun 1;248(4959):1058–1060. doi: 10.1126/science.2111582. [DOI] [PubMed] [Google Scholar]
  38. Sinha S., Dovey H. F., Seubert P., Ward P. J., Blacher R. W., Blaber M., Bradshaw R. A., Arici M., Mobley W. C., Lieberburg I. The protease inhibitory properties of the Alzheimer's beta-amyloid precursor protein. J Biol Chem. 1990 Jun 5;265(16):8983–8985. [PubMed] [Google Scholar]
  39. Sokoloff L. The F.O. Schmitt Lecture in Neuroscience 1980. The relationship between function and energy metabolism: its use in the localization of functional activity in the nervous system. Neurosci Res Program Bull. 1981 May;19(2):159–207. [PubMed] [Google Scholar]
  40. Stadtman E. R., Oliver C. N. Metal-catalyzed oxidation of proteins. Physiological consequences. J Biol Chem. 1991 Feb 5;266(4):2005–2008. [PubMed] [Google Scholar]
  41. Trapp G. A. Plasma aluminum is bound to transferrin. Life Sci. 1983 Jul 25;33(4):311–316. doi: 10.1016/s0024-3205(83)80002-2. [DOI] [PubMed] [Google Scholar]
  42. Wurtman R. J. Alzheimer's disease. Sci Am. 1985 Jan;252(1):62-6, 71-4. doi: 10.1038/scientificamerican0185-62. [DOI] [PubMed] [Google Scholar]
  43. Yates C. M., Butterworth J., Tennant M. C., Gordon A. Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias. J Neurochem. 1990 Nov;55(5):1624–1630. doi: 10.1111/j.1471-4159.1990.tb04948.x. [DOI] [PubMed] [Google Scholar]

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