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HEAVY METAL IONS BINDING TO AMYLOID-? PEPTIDES: BIOCHEMICAL AND BIOMEDICAL IMPLICATIONS
Abstract
Alzheimer?s disease (AD) is associated with conformational changes of amyloid-? peptides, which result in peptide oligomerization and fibril formation and, finally, in the appearance of senile plaques and extensive neuronal loss. However, the factors regulating the process of plaque-associated beta-amyloid peptide (A?) aggregation are only partly understood. Therefore, several ?-amyloid peptide fragments have been synthesized by SPPS according to Boc/Bzl strategy. Binding of metal ions to ?-amyloid peptides was studied by electrospray ion trap mass spectrometry (ESI-MS) at pH 7.4 or 6.6. Copper ions bind strongly and specifically to ?-amyloid(1-40) peptide and to its N- and C-terminal truncated versions. It was found that A?(1-10) peptide binds only one Cu(II) ion at pH 7.4. However, the intensity of peak corresponding to the doubly charged ion [M+Cu]2+ increases significantly with time and copper concentration. Nevertheless, the A?(1-16) peptide is able to bind one Cu(II) at 1:1 and 1:2 peptide-Cu ratio, and up to two Cu(II) at a peptide-Cu ratio of 1:10. Copper binding to A? peptides changed much the peptide conformation. During the binding of Cu(II) to N-terminal truncated ?-amyloid peptides, no copper ion was found to bind to A?(31-40) at 1:1 and 1:2 peptide: Cu(II) ratios. At 1:10 peptide-metal ion ratio, a low intense peak corresponding to [M+Cu]2+ ion was detected by ESI-MS after 7-8 min incubation of peptide-metal ion. A close relationship between pH, metal concentration and the proportion of conformers of A? fragments was found, as well. Our ESI-MS investigation showed that the C-terminal 31-40 sequence is not involved in copper binding. Our results also prove that Zn(II) has lower affinity toward A?-peptides as compared to Cu(II). At 1:10 peptide-Zn(II), no peak corresponding to the A?-peptides was detected by ESI-MS, where an aggregation process was suspected. These findings are discussed in the light of recent literature on neurodegeneration biochemistry.
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References11
Bush A.I., The metal theory of Alzheimer’s disease. Journal of Alzheimers Disease, 2013, vol. 33, pp. S277–S281.
Giacobini, E., Gold, G. Alzheimer disease therapy—moving from amyloid-β to tau. Nature Reviews Neurology, 2013, vol. 9, pp. 677-686.
Manea M., Schlosser G., Murariu, M., Time- and pH-dependent copper binding to Aβ(1–16) peptide: an electrospray ionization-mass spectrometric approach. International Journal of Peptide Research and Therapeutics, 2015, vol. 21, pp.125-131.
Tougu V., Karafin A., Palumaa, P., Binding of zinc (II) and copper (II) to the full-length Alzheimer’s amyloid-β peptide. Journal of Neurochemistry, 2008, vol. 104, pp. 1249-1259.
Murariu M., Dragan, E.S., Drochioiu, G., Electrospray ionization mass spectrometric approach of conformationally-induced metal binding to oligopeptides. European Journal of Mass Spectrometry, 2010, vol.16, pp. 511-521.
Korshavn K.J., Jang M., Kwak Y.J., Kochi A., Vertuani, S., Bhunia, A., Manfredini S., Ramamoorthy A., Lim M.H., Reactivity of metal-free and metal-associated amyloid-β with glycosylated polyphenols and their esterified derivatives. Scientific reports, 2015, vol. 5, art. 17842, DOI: 10.1038/srep17842.
Dai X., Sun Y., Gao Z., Jiang Z., Copper enhances amyloid-β peptide neurotoxicity and non β-aggregation. Journal of Molecular Neuroscience, 2010, vol. 41, pp. 66-73.
Barnham K.J., Bush A.I., Metals in Alzheimer's and Parkinson's diseases. Current Opinion in Chemical Biology, 2008, vol. 12, pp. 222-228.
Squitti R., Metals in Alzheimer’s disease: a systemic perspective. Front Biosci, 2012, vol. 17, pp. 451-472.
Drago D., Bolognin S., Zatta P., Role of metal ions in the Aβ oligomerization in Alzheimer's disease and in other neurological disorders. Current Alzheimer Research, 2008, vol. 5, pp. 500-507.
Syme C.D., Nadal R.C., Rigby, S.E., Viles, J.H., Copper binding to the amyloid-β (Aβ) peptide associated with Alzheimer's disease. Journal of Biological Chemistry, 2004, vol. 279, pp. 18169-18177.
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