Metal Ion Effects on Aβ and Tau Aggregation

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2018 Jan 6

PMID 29301328

Citations 63

Authors

Anne Claire Kim

Sungsu Lim

Yun Kyung Kim

Affiliations

Soon will be listed here.

Abstract

Amyloid and tau aggregation are implicated in manifold neurodegenerative diseases and serve as two signature pathological hallmarks in Alzheimer's disease (AD). Though aging is considered as a prominent risk factor for AD pathogenesis, substantial evidence suggests that an imbalance of essential biometal ions in the body and exposure to certain metal ions in the environment can potentially induce alterations to AD pathology. Despite their physiological importance in various intracellular processes, biometal ions, when present in excessive or deficient amounts, can serve as a mediating factor for neurotoxicity. Recent studies have also demonstrated the contribution of metal ions found in the environment on mediating AD pathogenesis. In this regard, the neuropathological features associated with biometal ion dyshomeostasis and environmental metal ion exposure have prompted widespread interest by multiple research groups. In this review, we discuss and elaborate on findings from previous studies detailing the possible role of both endogenous and exogenous metal ions specifically on amyloid and tau pathology in AD.

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References

Hirano T, Murakami M, Fukada T, Nishida K, Yamasaki S, Suzuki T . Roles of zinc and zinc signaling in immunity: zinc as an intracellular signaling molecule. Adv Immunol. 2008; 97:149-76. DOI: 10.1016/S0065-2776(08)00003-5. View

Yang D, Shi S, Zheng L, Yao T, Ji L . Mercury(II) promotes the in vitro aggregation of tau fragment corresponding to the second repeat of microtubule-binding domain: Coordination and conformational transition. Biopolymers. 2010; 93(12):1100-7. DOI: 10.1002/bip.21527. View

Forlenza O, De-Paula V, Diniz B . Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders. ACS Chem Neurosci. 2014; 5(6):443-50. PMC: 4063497. DOI: 10.1021/cn5000309. View

Yamamoto A, Shin R, Hasegawa K, Naiki H, Sato H, Yoshimasu F . Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer's disease. J Neurochem. 2002; 82(5):1137-47. DOI: 10.1046/j.1471-4159.2002.t01-1-01061.x. View

Lech T, Sadlik J . Copper concentration in body tissues and fluids in normal subjects of southern Poland. Biol Trace Elem Res. 2007; 118(1):10-5. DOI: 10.1007/s12011-007-0014-z. View

Sun X, Wei Y, Xiong Y, Wang X, Xie A, Wang X . Synaptic released zinc promotes tau hyperphosphorylation by inhibition of protein phosphatase 2A (PP2A). J Biol Chem. 2012; 287(14):11174-82. PMC: 3322889. DOI: 10.1074/jbc.M111.309070. View

Hare D, Ayton S, Bush A, Lei P . A delicate balance: Iron metabolism and diseases of the brain. Front Aging Neurosci. 2013; 5:34. PMC: 3715022. DOI: 10.3389/fnagi.2013.00034. View

Soragni A, Zambelli B, Mukrasch M, Biernat J, Jeganathan S, Griesinger C . Structural characterization of binding of Cu(II) to tau protein. Biochemistry. 2008; 47(41):10841-51. DOI: 10.1021/bi8008856. View

Grabrucker A, Rowan M, Garner C . Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review. Drug Deliv Lett. 2011; 1(1):13-23. PMC: 3220161. DOI: 10.2174/2210303111101010013. View

10.

Geddes J, Goodwin G, Rendell J, Azorin J, Cipriani A, Ostacher M . Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010; 375(9712):385-95. DOI: 10.1016/S0140-6736(09)61828-6. View

11.

Talmard C, Bouzan A, Faller P . Zinc binding to amyloid-beta: isothermal titration calorimetry and Zn competition experiments with Zn sensors. Biochemistry. 2007; 46(47):13658-66. DOI: 10.1021/bi701355j. View

12.

Guo C, Wang P, Zhong M, Wang T, Huang X, Li J . Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int. 2012; 62(2):165-72. DOI: 10.1016/j.neuint.2012.12.005. View

13.

Noy D, Solomonov I, Sinkevich O, Arad T, Kjaer K, Sagi I . Zinc-amyloid beta interactions on a millisecond time-scale stabilize non-fibrillar Alzheimer-related species. J Am Chem Soc. 2008; 130(4):1376-83. DOI: 10.1021/ja076282l. View

14.

Olivieri G, Brack C, Muller-Spahn F, Stahelin H, Herrmann M, Renard P . Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J Neurochem. 2000; 74(1):231-6. DOI: 10.1046/j.1471-4159.2000.0740231.x. View

15.

Gomez-Isla T, HOLLISTER R, West H, Mui S, Growdon J, Petersen R . Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann Neurol. 1997; 41(1):17-24. DOI: 10.1002/ana.410410106. View

16.

Alda M . Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry. 2015; 20(6):661-70. PMC: 5125816. DOI: 10.1038/mp.2015.4. View

17.

Boom A, Authelet M, Dedecker R, Frederick C, Van Heurck R, Daubie V . Bimodal modulation of tau protein phosphorylation and conformation by extracellular Zn2+ in human-tau transfected cells. Biochim Biophys Acta. 2008; 1793(6):1058-67. DOI: 10.1016/j.bbamcr.2008.11.011. View

18.

Sciacca M, Kotler S, Brender J, Chen J, Lee D, Ramamoorthy A . Two-step mechanism of membrane disruption by Aβ through membrane fragmentation and pore formation. Biophys J. 2012; 103(4):702-10. PMC: 3443794. DOI: 10.1016/j.bpj.2012.06.045. View

19.

Hane F, Hayes R, Lee B, Leonenko Z . Effect of Copper and Zinc on the Single Molecule Self-Affinity of Alzheimer's Amyloid-β Peptides. PLoS One. 2016; 11(1):e0147488. PMC: 4726707. DOI: 10.1371/journal.pone.0147488. View

20.

Goedert M, Cohen E, Jakes R, Cohen P . p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected]. FEBS Lett. 1992; 312(1):95-9. DOI: 10.1016/0014-5793(92)81418-l. View