Polish title: Zależność między strukturą kompleksów Cu(II) i Zn(II) z mutantami β-amyloidu a modulacją stresu oksydacyjnego w rodzinnej postaci choroby Alzheimera (FAD)
Funding source: National Science Centre Poland (NCN)
Project number: 2025/59/D/ST4/00979
PI: Magdalena Zofia Wiloch-Szyborska
Total funding: 1 220 732 PLN
Timeframe: 2026-10-01 – 2029-09-30
Short description
Familial Alzheimer’s Disease – When Memory Fades Too Early
Alzheimer’s disease is usually associated with elderly individuals. However, there exists an exceptionally challenging and rare form that appears much earlier, even in people in their thirties or forties. This is the so-called familial form of Alzheimer’s disease (FAD), which develops as a result of inherited mutations in specific genes. In contrast to the widely known late-onset form of the disease, FAD progresses very rapidly and aggressively. Sometimes, only six years pass from the first symptoms to the death.
A diagnosis of FAD is an enormous challenge for patients and their families. Individuals who are only just beginning their professional lives often have to stop working from one day to the next. There also arises the difficult question of having children, the risk of passing the disease to the next generation is high, and caring for a patient gradually requires full involvement of the family. Although science is making tremendous progress, there are still no effective therapies, and the only recommendations concern a healthy diet and physical activity, which can only slightly slow the development of the disease.
What Happens in the Brain? The Role of β-Amyloid and Metals
One of the main suspects in Alzheimer’s disease is a small peptide called β-amyloid (Aβ). In the brains of patients, excessive amounts of this peptide are produced, which promotes the formation of toxic aggregates that destroy neurons. It is also known that Aβ can bind metals such as copper and zinc. When this occurs, reactive oxygen species may form inside cells, damaging delicate neuronal structures.
In the familial form of the disease, β-amyloid is not identical to that found in other patients — altered versions of the peptide, the so-called Aβ mutants, are formed. Some studies suggest that they may be even more toxic. However, little is still known about how exactly they interact with metals and what chemical reactions occur in their presence. This is one of the greatest gaps in today’s understanding of FAD.
What Are Scientists Asking?
In our project, we aim to answer the question of how Aβ mutants bind metal ions and what properties the resulting complexes possess. We are interested in complexes containing a single metal as well as those in which copper and zinc are present simultaneously. We will investigate their stability, structure, and how they behave under conditions resembling the brain environment. To achieve this, we will use a range of advanced chemical techniques, including UV–Vis, NMR, and EPR spectroscopy, as well as ITC calorimetry and electrochemical studies.
A Novel Tool: Spectroelectrochemistry
A particularly important element of the project is the use of spectroelectrochemistry (SEC), a method that allows us to observe how the structure of complexes changes during controlled chemical reactions. We will combine electrochemical measurements with three different spectroscopic techniques: UV–Vis, Raman, and fluorescence. Such advanced experiments have never before been applied in research on amyloid peptides.
Why Is It Important?
The results of the project may help explain why FAD progresses so aggressively and what chemical processes drive neuronal degeneration. A better understanding of the role of metal ions and redox reactions in the toxicity of Aβ may, in the long term, open the way toward the development of new therapeutic strategies, which are currently completely lacking for the familial form of Alzheimer’s disease.
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