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HEAVY METAL IONS BINDING TO AMYLOID-? PEPTIDES: BIOCHEMICAL AND BIOMEDICAL IMPLICATIONS

Manuela Murariu

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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DOI resolver: doi.org/10.5593/sgem2018/6.2/s25.049

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