ESTONIAN ACADEMY
PUBLISHERS
eesti teaduste
akadeemia kirjastus
PUBLISHED
SINCE 1952
 
Proceeding cover
proceedings
of the estonian academy of sciences
ISSN 1736-7530 (Electronic)
ISSN 1736-6046 (Print)
Impact Factor (2022): 0.9
Metabolism of copper and possibilities for its regulation; pp. 382–392
PDF | https://doi.org/10.3176/proc.2023.4.03

Author
Peep Palumaa
Abstract

Copper is an indispensable biometal participating as a redox catalyst in many important biochemical processes. However, if uncontrolled, copper ions induce the formation of reactive oxygen species and become toxic. For this reason, cellular copper metabolism is tightly regulated and specific proteins – copper chaperones – participate in the metalation of cellular copper transporters and enzymes. The thermodynamic background for cellular copper distribution is known, and copper is driven to cellular destinations according to shallow affinity gradients. Copper metabolism is disturbed in the case of Wilson’s, Menkes, and Alzheimer’s disease (AD), characterized by copper overload, deficiency, and misdistribution, respectively. Wilson’s and Menkes disease could be treated by copper chelators and supplements, respectively; however, with AD, a search for effective molecular tools for the correction of copper metabolism is ongoing. One natural copper­binding ligand – α­-lipoic acid – has shown positive results in cellular and fruit fly models of AD and serves as a promising candidate for the regulation of copper metabolism in the case of AD.

References

1. Scheiber, I. F., Mercer, J. F. and Dringen, R. Metabolism and functions of copper in brain. Prog. Neurobiol., 2014, 116, 33–57.
https://doi.org/10.1016/j.pneurobio.2014.01.002

2. Tümer, Z. and Møller, L. B. Menkes disease. Eur. J. Hum. Genet., 2010, 18, 511–518.
https://doi.org/10.1038/ejhg.2009.187

3. D’Ambrosi, N. and Rossi, L. Copper at synapse: release, binding and modulation of neurotransmission. Neurochem. Int., 2015, 90, 36–45.
https://doi.org/10.1016/j.neuint.2015.07.006

4. Sies, H., Berndt, C. and Jones, D. P. Oxidative stress. Annu. Rev. Biochem., 2017, 86, 715–748.
https://doi.org/10.1146/annurev-biochem-061516-045037

5. Gaetke, L. M., Chow-Johnson, H. S. and Chow, C. K. Copper: toxicological relevance and mechanisms. Arch. Toxicol., 2014,88(11), 1929–1938.
https://doi.org/10.1007/s00204-014-1355-y

6. Blockhuys, S., Celauro, E., Hildesjö, C., Feizi, A., Stål, O., Fierro-González, J. C. et al. Defining the human copper proteome and analysis of its expression variation in cancers. Metallomics, 2017, 9(2), 112–123.
https://doi.org/10.1039/c6mt00202a

7. Balsano, C., Porcu, C. and Sideri, S. Is copper a new target to counteract the progression of chronic diseases? Metallomics, 2018,10, 1712–1722.
https://doi.org/10.1039/c8mt00219c

8. Eisses, J. F., Chi, Y. and Kaplan, J. H. Stable plasma membrane levels of hCTR1 mediate cellular copper uptake. J. Biol. Chem., 2005, 280(10), 9635–9639.
https://doi.org/10.1074/jbc.m500116200

9. Chen, J., Jiang, Y., Shi, H., Peng, Y., Fan, X. and Li, C. The molecular mechanisms of copper metabolism and its roles in human diseases. Pflugers Arch., 2020, 472(10), 1415–1429.
https://doi.org/10.1007/s00424-020-02412-2

10. Robinson, N. J. and Winge, D. R. Copper metallochaperones. Annu. Rev. Biochem., 2010, 79, 537–562.
https://doi.org/10.1146/annurev-biochem-030409-143539

11. Cobine, P. A., Pierrel, F. and Winge, D. R. Copper trafficking to the mitochondrion and assembly of copper metalloenzymes. Biochim. Biophys. Acta, 2006, 1763(7), 759–772.
https://doi.org/10.1016/j.bbamcr.2006.03.002

12. Vaher, M., Romero-Isart, N., Vašák, M. and Palumaa, P. Reactivity of Cd7-metallothionein with Cu(II) ions: evidence for a cooperative formation of Cd3,Cu(I)5-metallothionein. J. Inorg. Biochem., 2001, 83(1), 1–6.
https://doi.org/10.1016/S0162-0134(00)00183-5

13. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R. and Turner, N. D. Glutathione metabolism and its implications for health. J. Nutr., 2004, 134(3), 489–492.
https://doi.org/10.1093/jn/134.3.489

14. Banci, L., Bertini, I., Ciofi-Baffoni, S., Kozyreva, T., Zovo, K. and Palumaa, P. Affinity gradients drive copper to cellular destinations. Nature, 2010, 465, 645–648.
https://doi.org/10.1038/nature09018

15. Smirnova, J., Kabin, E., Järving, I., Bragina, O., Tõugu, V., Plitz, T. et al. Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent. Sci. Rep., 2018, 8, 1463.
https://doi.org/10.1038/s41598-018-19873-2

16. Meloni, G., Faller, P. and Vašák, M. Redox silencing of copper in metal-linked neurodegenerative disorders: reaction of Zn7metallothionein-3 with Cu2+ ions. J. Biol. Chem., 2007, 282(22), 16068–16078.
https://doi.org/10.1074/jbc.M701357200

17. Rae, T. D., Schmidt, P. J., Pufahl, R. A., Culotta, V. C. and O’Halloran, T. V. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science, 1999, 284(5415), 805–808.
https://doi.org/10.1126/science.284.5415.805

18. Cabrera, A., Alonzo, E., Sauble, E., Chu, Y. L., Nguyen, D., Linder, M. C. et al. Copper binding components of blood plasma and organs, and their responses to influx of large doses of (65)Cu, in the mouse. Biometals, 2008, 21(5), 525–543.
https://doi.org/10.1007/s10534-008-9139-6

19. Linder, M. C. Ceruloplasmin and other copper binding components of blood plasma and their functions: an update. Metallomics, 2016, 8(9), 887–905.
https://doi.org/10.1039/c6mt00103c

20. Kirsipuu, T., Zadorožnaja, A., Smirnova, J., Friedemann, M., Plitz, T., Tõugu, V. et al. Copper(II)-binding equilibria in human blood. Sci. Rep., 2020, 10, 5686.
https://doi.org/10.1038/s41598-020-62560-4

21. Samygina, V. R., Sokolov, A. V., Bourenkov, G., Petoukhov, M. V., Pulina, M. O., Zakharova, E. T. et al. Ceruloplasmin: macromolecular assemblies with iron-containing acute phase proteins. PLoS One, 2013, 8(7), e67145.
https://doi.org/10.1371/journal.pone.0067145

22. Członkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V. et al. Wilson disease. Nat. Rev. Dis. Primers, 2018,4, 21.
https://doi.org/10.1038/s41572-018-0018-3

23. Bull, P. C., Thomas, G. R., Rommens, J. M., Forbes, J. R. and Cox, D. W. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat. Genet., 1993, 5(4), 327–337.
https://doi.org/10.1038/ng1293-327

24. Tanzi, R. E., Petrukhin, K., Chernov, I., Pellequer, J. L., Wasco, W., Ross, B. et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat. Genet., 1993, 5(4), 344–350.
https://doi.org/10.1038/ng1293-344

25. Terada, K., Kawarada, Y., Miura, N., Yasui, O., Koyama, K. and Sugiyama, T. Copper incorporation into ceruloplasmin in rat livers. Biochim. Biophys. Acta., 1995, 1270(1), 58–62.
https://doi.org/10.1016/0925-4439(94)00072-x

26. Terada, K., Nakako, T., Yang, X. L., Iida, M., Aiba, N., Minamiya, Y. et al. Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA. J. Biol. Chem., 1998, 273(3), 1815–1820.
https://doi.org/10.1074/jbc.273.3.1815

27. Polishchuk, E. V., Concilli, M., Iacobacci, S., Chesi, G., Pastore, N., Piccolo, P. et al. Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Dev. Cell, 2014. 29(6), 686–700.
https://doi.org/10.1016/j.devcel.2014.04.033

28. Roberts, E. A. and Schilsky, M. L. Diagnosis and treatment of Wilson disease: an update. Hepatology, 2008, 47(6), 2089–2111.
https://doi.org/10.1002/hep.22261

29. Patil, M., Sheth, K. A., Krishnamurthy, A. C. and Devarbhavi, H. A review and current perspective on Wilson disease, J. Clin. Exp. Hepatol., 2013, 3(4), 321–336.
https://doi.org/10.1016/j.jceh.2013.06.002

30. Barber, R. G., Grenier, Z. A. and Burkhead, J. L. Copper toxicity is not just oxidative damage: zinc systems and insight from Wilson disease. Biomedicines, 2021, 9(3), 316.
https://doi.org/10.3390/biomedicines9030316

31. Merle, U., Eisenbach, C., Weiss, K. H., Tuma, S. and Stremmel, W. Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson’s disease. J. Hepatol., 2009, 51(5), 925–930.
https://doi.org/10.1016/j.jhep.2009.06.022

32. Xu, R., Jiang, Y.-F., Zhang, Y.-H. and Yang, X. The optimal threshold of serum ceruloplasmin in the diagnosis of Wilson’s disease: a large hospital-based study. PLoS One, 2018, 13, e0190887.
https://doi.org/10.1371/journal.pone.0190887

33. Walshe, J. M. Serum ‘free’ copper in Wilson disease. QJM, 2012, 105(5), 419–423.
https://doi.org/10.1093/qjmed/hcr229

34. Camakaris, J., Petris, M. J., Bailey, L., Shen, P., Lockhart, P., Glover, T. W. et al. Gene amplification of the Menkes (MNK; ATP7A) P-type ATPase gene of CHO cells is associated with copper resistance and enhanced copper efflux. Hum. Mol. Genet., 1995,4(11), 2117–2123.
https://doi.org/10.1093/hmg/4.11.2117

35. Monty, J. F., Llanos, R. M., Mercer, J. F. and Kramer, D. R. Copper exposure induces trafficking of the Menkes protein in intestinal epithelium of ATP7A transgenic mice. J. Nutr., 2005, 135(12), 2762–2766.
https://doi.org/10.1093/jn/135.12.2762

36. Petris, M. J., Mercer, J. F., Culvenor, J. G., Lockhart, P., Gleeson, P. A. and Camakaris, J. Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. EMBO J., 1996, 15(22), 6084–6095.

37. Fujisawa, C., Kodama, H., Sato, Y., Mimaki, M., Yagi, M., Awano, H. et al. Early clinical signs and treatment of Menkes disease. Mol. Genet. Metab. Rep., 2022, 31, 100849.
https://doi.org/10.1016/j.ymgmr.2022.100849

38. Anand, R., Gill, K. D. and Mahdi, A. A. Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology, 2014, 76(Pt A), 27–50.

39. Alzheimer’s Association. 2023 Alzheimer’s Disease Facts and Figures
https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf (accessed 2023-09-22).

40. Selkoe, D. J. Alzheimer’s disease. Cold Spring Harb. Perspect. Biol., 2011, 3(7), a004457.
https://doi.org/10.1101/cshperspect.a004457

41. Hardy, J. A. and Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science, 1992, 256(5054), 184–185.
https://doi.org/10.1126/science.1566067

42. Selkoe, D. J. and Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med., 2016, 8(6), 595–608.
https://doi.org/10.15252/emmm.201606210

43. Bucossi, S., Ventriglia, M., Panetta, V., Salustri, C., Pasqualetti, P., Mariani, S. et al. Copper in Alzheimer’s disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies. J. Alzheimers Dis., 2011, 24(1), 175–185.
https://doi.org/10.3233/jad-2010-101473

44. Li, D.-D., Zhang, W., Wang, Z.-Y. and Zhao, P. Serum copper, zinc, and iron levels in patients with Alzheimer’s disease: a meta-analysis of case-control studies. Front. Aging Neurosci., 2017, 9, 300.
https://doi.org/10.3389/fnagi.2017.00300

45. Schrag, M., Mueller, C., Oyoyo, U., Smith, M. A. and Kirsch, W. M. Iron, zinc and copper in the Alzheimer’s disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog. Neurobiol., 2011, 94(3), 296–306.
https://doi.org/10.1016/j.pneurobio.2011.05.001

46. Xu, J., Church, S. J., Patassini, S., Begley, P., Waldvogel, H. J., Curtis, M. A. et al. Evidence for widespread, severe brain copper deficiency in Alzheimer’s dementia. Metallomics, 2017, 9(8), 1106–1119.
https://doi.org/10.1039/c7mt00074j

47. Squitti, R., Ventriglia, M., Simonelli, I., Bonvicini, C., Costa, A., Perini, G. et al. Copper imbalance in Alzheimer’s disease: meta-analysis of serum, plasma, and brain specimens, and replication study evaluating ATP7B gene variants. Biomolecules, 2021,11(7), 960.
https://doi.org/10.3390/biom11070960

48. Madarić, A., Ginter, E. and Kadrabová, J. Serum copper, zinc and copper/zinc ratio in males: influence of aging. Physiol. Res., 1994, 43(2), 107–111.

49. Bonilla, E., Salazar, E., Villasmil, J. J., Villalobos, R., Gonzalez, M. and Davila, J. O. Copper distribution in the normal human brain. Neurochem. Res., 1984, 9(11), 1543–1548.
https://doi.org/10.1007/bf00964589

50. Squitti, R., Polimanti, R., Siotto, M., Bucossi, S., Ventriglia, M., Mariani, S. et al. ATP7B variants as modulators of copper dyshomeostasis in Alzheimer’s disease. Neuromol. Med., 2013, 15, 515–522.
https://doi.org/10.1007/s12017-013-8237-y

51. Squitti, R. Metals in Alzheimer’s disease: a systemic perspective. Front. Biosci., 2012, 17(2), 451–472.
https://doi.org/10.2741/3938

52. Litwin, T., Dziezyc, K. and Członkowska, A. Wilson disease – treatment perspectives. Ann. Transl. Med., 2019, 7(Suppl. 2), S68.
https://doi.org/10.21037/atm.2018.12.09

53. Vairo, F. P. E., Chwal, B. C., Perini, S., Ferreira, M. A. P., de Freitas Lopes, A. C. and Saute, J. A. M. A systematic review and evidence-based guideline for diagnosis and treatment of Menkes disease. Mol. Genet. Metab., 2019, 126(1), 6–13.
https://doi.org/10.1016/j.ymgme.2018.12.005

54. Walshe, J. M. Penicillamine, a new oral therapy for Wilson’s disease. Am. J. Med., 1956, 21(4), 487–495.
https://doi.org/10.1016/0002-9343(56)90066-3

55. Walshe, J. M. Penicillamine: the treatment of first choice for patients with Wilson’s disease. Mov. Disord., 1999, 14(4), 545–550.
https://doi.org/10.1002/1531-8257(199907)14:4%3C545::aid-mds1001%3E3.0.co;2-u

56. Walshe, J. M. Treatment of Wilson’s disease with trientine (triethylene tetramine) dihydrochloride. Lancet, 1982, 1(8273), 643–647.
https://doi.org/10.1016/s0140-6736(82)92201-2

57. Brewer, G. J., Hedera, P., Kluin, K. J., Carlson, M., Askari, F., Dick, R. B. et al. Treatment of Wilson disease with ammonium tetrathiomolybdate III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch. Neurol., 2003, 60(3), 379–385.
https://doi.org/10.1001/archneur.60.3.379

58. Weiss, K. H., Askari, F. K., Ferenci, P., Ala, A., Czlonkowska, A., Nicholl, D. et al. WTX101 in patients newly diagnosed with Wilson’s disease: final results of a global, prospective phase 2 trial. J. Hepatol., 2017, 66(1), S88.
http://doi.org/10.1016/S0168-8278(17)30440-3

59. Rodriguez-Castro, K. I., Hevia-Urrutia, F. J. and Sturniolo, G. C. Wilson’s disease: A review of what we have learned. World J. Hepatol., 2015, 7(29), 2859–2870.
https://doi.org/10.4254/wjh.v7.i29.2859

60. Cumings, J. N. The effects of B.A.L. in hepatolenticular degeneration. Brain, 1951, 74(1), 10–22.
https://doi.org/10.1093/brain/74.1.10

61. Li, W.-J., Chen, C., You, Z.-F., Yang, R.-M. and Wang, X.-P. Current drug managements of Wilson’s disease: from west to east. Curr. Neuropharmacol., 2016, 14(4), 322–325.
https://doi.org/10.2174/1570159x14666151130222427

62. Aaseth, J., Skaug, M. A., Cao, Y. and Andersen, O. Chelation in metal intoxication--principles and paradigms. J. Trace Elem. Med. Biol., 2015, 31, 260–266.
https://doi.org/10.1016/j.jtemb.2014.10.001

63. Flora, S. J. S. and Pachauri, V. Chelation in metal intoxication. Int. J. Environ. Res. Public Health, 2010, 7(7), 2745–2788.
https://doi.org/10.3390/ijerph7072745

64. Rooney, J. P. K. The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury. Toxicology, 2007, 234(3), 145–156.
https://doi.org/10.1016/j.tox.2007.02.016

65. Kreuder, J., Otten, A., Fuder, H., Tümer, Z., Tønnesen, T., Horn, N. et al. Clinical and biochemical consequences of copper-histidine therapy in Menkes disease. Eur. J. Pediatr., 1993, 152(10), 828–832.
https://doi.org/10.1007/bf02073380

66. Christodoulou, J., Danks, D. M., Sarkar, B., Baerlocher, K. E., Casey, R., Horn, N. et al.. Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients. Am. J. Med. Genet., 1998, 76(2), 154–164.

67. Fasae, K. D., Abolaji, A. O., Faloye, T. R., Odunsi, A. Y., Oyetayo, B. O., Enya, J. I. et al. Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: limitations, and current and future perspectives. J. Trace Elem. Med. Biol., 2021, 67, 126779.
https://doi.org/10.1016/j.jtemb.2021.126779

68. Kessler, H., Pajonk, F. G., Bach, D., Schneider-Axmann, T., Falkai, P., Herrmann, W. et al. Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial. J. Neural. Transm., 2008, 115(12), 1651–1659.
https://doi.org/10.1007/s00702-008-0136-2

69. Kessler, H., Bayer, T. A., Bach, D., Schneider-Axmann, T., Supprian, T., Herrmann, W. et al. Intake of copper has no effect on cognition in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial. J. Neural. Transm., 2008, 115(8), 1181–1187.
https://doi.org/10.1007/s00702-008-0080-1

70. Squitti, R., Rossini, P. M., Cassetta, E., Moffa, F., Pasqualetti, P., Cortesi, M. et al. d-penicillamine reduces serum oxidative stress in Alzheimer’s disease patients. Eur. J. Clin. Invest., 2002, 32(1), 51–59.
https://doi.org/10.1046/j.1365-2362.2002.00933.x

71. Barnham, K. J., Masters, C. L. and Bush, A. I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov., 2004,3(3), 205–214.
https://doi.org/10.1038/nrd1330

72. Bush, A. I. Drug development based on the metals hypothesis of Alzheimer’s disease. J. Alzheimers Dis., 2008, 15(2), 223–240.
https://doi.org/10.3233/JAD-2008-15208

73. Sampson, E. L., Jenagaratnam, L. and McShane, R. Metal protein attenuating compounds for the treatment of Alzheimer’s dementia. Cochrane Database Syst. Rev., 2014, CD005380.
https://doi.org/10.1002/14651858.cd005380.pub5

74. Jenagaratnam, L. and McShane, R. Clioquinol for the treatment of Alzheimer’s disease. Cochrane Database Syst. Rev., 2006, CD005380.
https://doi.org/10.1002/14651858.cd005380.pub2

75. Adlard, P. A. and Bush, A. I. Metals and Alzheimer’s disease: how far have we come in the clinic? J. Alzheimers Dis., 2018,62(3), 1369–1379.
https://doi.org/10.3233%2FJAD-170662

76. Lannfelt, L., Blennow, K., Zetterberg, H., Batsman, S., Ames, D., Harrison, J. et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol., 2008, 7(9), 779–786.
https://doi.org/10.1016/s1474-4422(08)70167-4

77. Faux, N. G., Ritchie, C. W., Gunn, A., Rembach, A., Tsatsanis, A., Bedo, J. et al. PBT2 rapidly improves cognition in Alzheimer’s disease: additional phase II analyses. J. Alzheimers Dis., 2010, 20(2), 509–516.
https://doi.org/10.3233/jad-2010-1390

78. Robert, A., Liu, Y., Nguyen, M. and Meunier, B. Regulation of copper and iron homeostasis by metal chelators: a possible chemotherapy for Alzheimer’s disease. Acc. Chem. Res., 2015, 48(5), 1332–1339.
https://doi.org/10.1021/acs.accounts.5b00119

79. Liu, Y., Nguyen, M., Robert, A. and Meunier, B. Metal ions in Alzheimer’s disease: a key role or not? Acc. Chem. Res., 2019,52(7), 2026–2035.
https://doi.org/10.1021/acs.accounts.9b00248

80. Esmieu, C., Guettas, D., Conte-Daban, A., Sabater, L., Faller, P. and Hureau, C. Copper-targeting approaches in Alzheimer’s disease: how to improve the fallouts obtained from in vitro studies. Inorg. Chem., 2019, 58(20), 13509–13527.
https://doi.org/10.1021/acs.inorgchem.9b00995

81. Dedeoglu, A., Cormier, K., Payton, S., Tseitlin, K. A., Kremsky, J. N., Lai, L. et al. Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer’s amyloidogenesis. Exp. Gerontol., 2004, 39(11–12), 1641–1649.
https://doi.org/10.1016/j.exger.2004.08.016

82. Rodríguez-Rodríguez, C., Sánchez de Groot, N., Rimola, A., Alvarez-Larena, A., Lloveras, V., Vidal-Gancedo, J. et al. Design, selection, and characterization of thioflavin-based intercalation compounds with metal chelating properties for application in Alzheimer’s disease. J. Am. Chem. Soc., 2009, 131(4), 1436–1451.
https://doi.org/10.1021/ja806062g

83. Choi, J.- S., Braymer, J. J., Nanga, R. P. R., Ramamoorthy, A. and Lim, M. H. Design of small molecules that target metal-A{beta} species and regulate metal-induced A{beta} aggregation and neurotoxicity. Proc. Natl. Acad. Sci. U. S. A., 2010, 107(51), 21990–21995.
https://doi.org/10.1073/pnas.1006091107

84. Zhao, J., Shi, Q., Tian, H., Li, Y., Liu, Y., Xu, Z. et al. TDMQ20, a specific copper chelator, reduces memory impairments in Alzheimer’s disease mouse models. ACS Chem. Neurosci., 2021, 12(1), 140–149. 
https://doi.org/10.1021/acschemneuro.0c00621

85. Wang, C.-Y., Xie, J.-W., Xu, Y., Wang, T., Cai, J.-H., Wang, X. et al. Trientine reduces BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-kappaB pathway in a transgenic mouse model of Alzheimer’s disease. Antioxid. Redox Signal., 2013,19(17), 2024–2039.
https://doi.org/10.1089/ars.2012.5158

86. Squitti, R., Pal, A., Picozza, M., Avan, A., Ventriglia, M., Rongioletti, M. C. et al. Zinc therapy in early Alzheimer’s disease: safety and potential therapeutic efficacy. Biomolecules, 2020, 10(8).
https://doi.org/10.3390/biom10081164

87. Brewer, G. J. Copper excess, zinc deficiency, and cognition loss in Alzheimer’s disease. Biofactors, 2012, 38(2), 107–113.
https://doi.org/10.1002/biof.1005

88. Camarata, M. A., Ala, A. and Schilsky, M. L. Zinc maintenance therapy for Wilson disease: a comparison between zinc acetate and alternative zinc preparations. Hepatol. Commun., 2019, 3(8), 1151–1158.
https://doi.org/10.1002/hep4.1384

89. Metsla, K., Kirss, S., Laks, K., Sildnik, G., Palgi, M., Palumaa, T. et al. Alpha-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease. J. Alzheimers Dis., 2022, 85(2), 715–728.
https://doi.org/10.3233/jad-215026

90. Shay, K. P., Moreau, R. F., Smith, E. J., Smith, A. R. and Hagen, T. M. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta, 2009, 1790(10), 1149–1160.
https://doi.org/10.1016/j.bbagen.2009.07.026

91. Rowland, E. A., Snowden, C. K. and Cristea, I. M. Protein lipoylation: an evolutionarily conserved metabolic regulator of health and disease. Curr. Opin. Chem. Biol., 2018, 42, 76–85.
https://doi.org/10.1016/j.cbpa.2017.11.003

92. Bjørklund, G., Aaseth, J., Crisponi, G., Rahman, M. M. and Chirumbolo, S. Insights on alpha lipoic and dihydrolipoic acids as promising scavengers of oxidative stress and possible chelators in mercury toxicology. J. Inorg. Biochem., 2019, 195, 111–119.
https://doi.org/10.1016/j.jinorgbio.2019.03.019

93. Stoll, S., Hartmann, H., Cohen, S. A. and Müller, W. E. The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits. Pharmacol. Biochem. Behav., 1993, 46(4), 799–805.
https://doi.org/10.1016/0091-3057(93)90204-7

94. Quinn, J. F., Bussiere, J. R., Hammond, R. S., Montine, T. J., Henson, E., Jones, R. E. et al. Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol. Aging, 2007, 28(2), 213–225.
https://doi.org/10.1016/j.neurobiolaging.2005.12.014

95. Mijnhout, G. S., Kollen, B. J., Alkhalaf, A., Kleefstra, N. and Bilo, H. J. G. Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int. J. Endocrinol., 2012, 2012, 456279.
https://doi.org/10.1155/2012/456279

96. Hager, K., Kenklies, M., McAfoose, J., Engel, J. and Münch, G. Alpha-lipoic acid as a new treatment option for Alzheimer’s disease – a 48 months follow-up analysis. J. Neural. Transm. Suppl., 2007(72), 189–193. https://doi.org/10.1007/978-3-211-73574-9_24

97. Maczurek, A., Hager, K., Kenklies, M., Sharman, M., Martins, R., Engel, J. et al. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease. Adv. Drug Deliv. Rev., 2008, 60(13–14), 1463–1470.
https://doi.org/10.1016/j.addr.2008.04.015

98. Fava, A., Pirritano, D., Plastino, M., Cristiano, D., Puccio, G., Colica, C. et al. The effect of lipoic acid therapy on cognitive functioning in patients with Alzheimer’s disease. J. Neurodegener. Dis., 2013, 2013, 454253.
https://doi.org/10.1155/2013/454253

99. Appleby, B. S., Nacopoulos, D., Milano, N., Zhong, K. and Cummings, J. L. A review: treatment of Alzheimer’s disease discovered in repurposed agents. Dement. Geriatr. Cogn. Disord., 2013, 35(1–2), 1–22.
https://doi.org/10.1159/000345791

100. Ziegler, D., Hanefeld, M., Ruhnau, K. J., Meissner, H. P., Lobisch, M., Schütte, K. et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia, 1995, 38(12), 1425–1433.
https://doi.org/10.1007/bf00400603

101. Lipinski, C. A., Lombardo, F., Dominy, B. W. and Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug. Deliv. Rev., 2001, 46(1–3), 3–26.
https://doi.org/10.1016/s0169-409x(00)00129-0

102. Tsvetkov, P., Coy, S., Petrova, B., Dreishpoon, M., Verma, A., Abdusamad, M. et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586), 1254–1261.
https://doi.org/10.1126/science.abf0529

Back to Issue