Cracking the complex complex – the step toward inhibition of Alzheimer’s disease

Alzheimer's disease (AD) is one of the most common and challenging neurodegenerative diseases globally. It mostly affects older adults, causing irreversible changes in the brain that result in the progression of dementia, behavioral impairments, and worsening of daily living skills. Although Alzheimer's disease has been studied for over a century, there is still no effective treatment. Recent research demonstrated by interdisciplinary team of scientists from the Institute of Physical Chemistry, Polish Academy of Sciences in Poland and University of Burgos in Spain, highlight the important role of using combined analytical techniques to investigate potential drug candidates. They show how a novel molecule – TDMQ20 – that is proposed as a drug to treat AD, interacts with copper ions, decreasing the harmful effect on neurons. Let’s take a closer look at their breakthrough.

 

It is widely known that Alzheimer's disease is mainly associated with the overproduction of β-amyloid peptides and damage caused by oxidative stress. For years, scientists have been trying to understand why nerve cells degrade so rapidly in Alzheimer's disease, and many efforts have been made not only to monitor the progression of such disease development. This also applies to the improvement of effective diagnostics at an early stage and finding a clear solution treating it. If the riddle of the pathological mechanisms behind Alzheimer’s disease progression is ever solved, it would open a path toward significantly improving the quality of life for patients. Among many factors enhancing the progression of AD is copper, the same trace element that is essential for biochemical processes acting as a cofactor for enzymes involved in energy production, neuronal signaling, and many more processes, including defense against oxidative stress. However, dysregulation of copper levels in the body can lead to aggregation of proteins that contribute to neurodegeneration, just like when copper reacts with amyloids in the brain, forming β-amyloid-copper complexes. Copper can overstimulate the production of free radicals, promoting the oxidative stress that, in turn, directly affects neurons, often leading to irreversible pathological changes.

In search of ways to inhibit this process, researchers are analyzing various chemical compounds capable of controlling copper reactions in the biological tissues. One promising candidate is TDMQ20 - tetradentate mono-quinoline, a molecule that can bind copper ions selectively, working as a chelator and thus modulating the copper toxicity in neurodegenerative diseases. Recent studies proposed by scientists from the Institute of Physical Chemistry, Polish Academy of Sciences (IPC PAS) under the international collaboration with scientist from University of Burgos in Spain show a novel approach to studying copper chelators that may serve as potential drug candidates against Alzheimer’s disease. Importantly, their research is a continuation of earlier work in which they used spectroelectrochemistry for the first time as a tool to study the redox properties of TDMQ20. After conducting detailed studies on the redox properties of TDMQ20, it becomes clear how copper behaves when bound to TDMQ20, in terms of the oxidation-reduction (redox) reactivity that plays a crucial role in the therapeutic safety of the tested binder. Studies show the possibility of inactivating copper in Cu(II)-TDMQ20, where the complex does not generate harmful reactive oxygen species (ROS).

Dr. Magdalena Wiloch says: “Based on voltammetry, we determined the oxidation and reduction potentials for this complex. For the cathodic potentials, the reduction of the, copper ion occurs at very low potential values. This means that under normal conditions in the human body, this process does not take place. As a result, the Cu–TDMQ20 complex itself does not contribute to the oxidative stress that damages neurons.”

To verify this, the researchers used a set of methods combining an electrochemical approach and spectroscopy. In other words, they observed how the Cu(II)-TDMQ20 complex reacts to changes in electrical voltage and how its optical properties change. This allowed them to observe what happens to the molecule during its oxidation and reduction processes. It turned out that the Cu(II)- TDMQ20 complex exhibits redox behavior, where the redox properties clearly depend on the pH of the solution. The measurements in various pH levels are crucial for understanding even subtle experimental parameters to mimic the different processes that would take place in the different parts of a cell that differ in pH, which can possibly affect the stability and activity of the proposed TDMQ20 molecule.

Research has also shown that when the complex is oxidized, the structure does not disintegrate immediately - on the contrary, copper remains bound to the ligand, although the nature of this bond changes. Electrochemical modelling has made it possible to determine the rate of some key processes, including the internal transfer of electrons between the ligand and the copper ion. Such information is extremely important because it determines whether the molecule can function stably and predictably under biological conditions.

“UV-VIS spectroelectrochemical experiments and computer simulations allowed us to better understand the electrochemical transformations of Cu(II)-TDMQ20. UV-VIS SEC confirmed the formation of one or several new Cu(II)-TDMQ20⁺ complexes in which the ligand is in an oxidized form. In the cathodic potential range, we observed the reduction of the metal center, which is also pH dependent.” – adds dr. Martin Perez-Estabenez.

Why is all this important? If TDMQ20 can indeed control copper reactions without generating dangerous oxidized forms, it may help reduce the oxidative stress associated with the reactivity of the copper-amyloid complexes. The electrochemical results show a breakthrough in the understanding of ligand–metal interactions in the TDMQ20-mediated system. Researchers from IPC PAS have proposed, for the first time, a spectroelectrochemical approach for studying TDMQ20 and Cu-TDMQ20 complexes, revealing highly effective ligand–metal interactions that have significant implications not only for bioinorganic chemistry and Alzheimer’s disease therapeutics.

This work identifies structural changes upon applied potential, offering fresh insight into how coordination complexes can reorganize. At the same time, their studies highlight the role of TDMQ20 as a promising candidate for inhibiting Alzheimer's disease progression. Besides the scientific findings, the authors of the research also point out that scientific progress significantly depends on interdisciplinary collaborations. Researchers stress that studies performed in international cooperation allow them to obtain results that would simply be impossible or taking much longer for a single group to achieve on its own. The demonstrated work shows how combining expertise from different fields, such as electrochemistry, spectroscopy, and computational modelling, enables insights that none of these fields could achieve alone. Secondly, they demonstrate that spectroelectrochemistry is a powerful tool, providing support in understanding how drug candidates behave under physiologically relevant redox conditions. Their studies emphasize the combining two techniques within a single experiment. This integrated spectroelectrochemical approach makes it possible to obtain much broader information about structural changes under redox reactions. Exploring the oxidation and reduction potentials of biologically active molecules provides information directly connected to their activity inside the body. Yet, such an approach is still rarely applied in drug-related studies.

This work has been financially supported by the National Science Centre Poland, within the Sonatina project 2021/40/C/ST4/00090

 

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