Behind the Science: Copper Binding to Amyloid-β Peptides

Behind the Science: Copper Binding to Amyloid-β Peptides

Author: Arlette Itken-Fuder, Christelle Hureau

Dr. Christelle Hureau, University of Toulouse, France, talks to Dr. Arlette Itken-Fuder, Senior Associate Editor of the European Journal of Inorganic Chemistry, about her article on the binding of copper(II) to amyloid-β peptides. The peptide is highly relevant to research on Alzheimer’s disease. In her microreview, Dr. Hureau describes the effects of different forms of the peptide on the Cu(II) binding site and affinity. She also looks at the production of reactive oxygen species and the aggregation of peptides.

Dr. Hureau, you are working on the binding of copper(II) to amyloid-β peptides. When and how did you start working in this area?

I started working on this exciting field ten years ago when I was recruited at the Laboratoire de Chimie de Coordination in Toulouse as a permanent researcher. In the Alzheimer & Amyloid group, we study how metal ions, including copper ions, interact with the amyloid-β peptide involved in Alzheimer’s disease (AD) and how this relates to oxidative stress and senile plaque formation. We are also interested in the development of new therapeutic approaches based on selective copper targeting and on new diagnostic tools.

Why is this particular topic of interest?

There are many hypotheses regarding the causes and progression of Alzheimer’s disease. According to one of them, the accumulation of the amyloid-β peptide, the main constituent of the senile plaque detected in AD brains, is an important aspect. Copper ions are also found in high amounts in the senile plaques, and the copper ions have the ability to participate in oxidative stress. Hence, it is hypothesized that the interaction between copper ions and the amyloid-β peptide is harmful.

Up to now, most studies have taken into account only one kind of amyloid-β peptide, while there are several kinds of it. This can induce some bias in the conclusions. It is thus important to study the interaction of copper ions with other, shorter, forms of the amyloid-β peptide as well.

How do the types of amyloid-β peptides differ in terms of activity?

The amyloid-β peptide exists in several forms of different lengths. On the one hand, the C-terminal part is quite heterogeneous, with peptides ending at positions 39 to 43. The longer the peptide, the more prone to aggregation it is.

On the other hand, N-terminal deletions of the three and ten first amino acid residues lead to a peptide with modified Cu(II) binding ability. This, in turn, induces a different catalytic activity for the formation of Reactive Oxygen Species (ROS) participating in oxidative stress and the resulting toxicity. The N-terminally truncated peptides have less of a tendency to produce ROS than the full-length ones.

Why was your attention focused on this particular area?

During the last years, chemists and biochemists have paid particular attention to the full-length peptide, while its truncated forms have been overlooked. Considering that full-length and truncated forms do exhibit different ROS production properties, it makes sense to investigate Cu(II) binding and the associated toxicity more deeply.

How big an impact could this work have?

The most important impact may be related to the design of new chelators in the context of Alzheimer’s disease. Indeed, one of the consequences of the different Cu(II) binding ability between the full-length and truncated peptides is the value of the Cu(II) affinity. It increases by four orders of magnitude in the truncated peptides.

Which aspects will you investigate next?

The truncated peptides being processed by enzymes. One can imagine playing with the activity of such enzymes to regulate their formation and thus the associated production of ROS from a therapeutic perspective. Zinc ions are also involved in Alzheimer’s disease. We are currently studying the interaction of the truncated peptides with zinc, which may be of relevance as well.


The article they talked about

 

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