The molecular mechanisms of the onset of Alzheimer's disease
Employees of the Faculty of Fundamental Medicine of the Lomonosov Moscow State University determined the structure of the peptide complex, which is formed in the brain in the early stages of Alzheimer's disease. The results of the study will help in the development of compounds that can stop the development of this disease.
A group of researchers for several years studied the molecular mechanism of zinc-dependent aggregation of beta-amyloid peptide, which is formed in the brain in the early stages of the disease in carriers of the Taiwan mutation. They described the structure of the formed complexes and established the role of zinc ions (Zn2 +) in their formation. The carriers of such mutations start to develop Alzheimer's disease in a relatively young age. The authors found that the structure of beta-amyloid complexes from mutant peptides is more stable than that of complexes from normal peptides.
Beta-amyloid is a small peptide that performs important physiological functions, for example, protects the brain from potential pathogens. After performing its functions, the peptide is usually being disposed. However, in some cases, its molecules begin to bind to each other, forming complexes that are toxic to neurons. The processes of beta-amyloid peptide aggregation into complexes are initiated by metal ions.
The authors state that interactions of fragments of peptides with zinc ions led to the formation of a stable complex in which two peptide chains are firmly fastened by two zinc ions. Similar binuclear structures were never described previously. It is important to note that the interaction of metal ions with beta-amyloid usually leads to a variety of different conformations of the peptide chain. The resulting complex "breathes" from one conformation to another. In the case of the Taiwan mutation, a single conformation was observed, which allowed to determine its structure with high accuracy by nuclear magnetic resonance.
The obtained results will help in the development of compounds capable of blocking the zinc-dependent aggregation of beta-amyloid and, thereby, stop the development of Alzheimer's disease at an early stage. Based on the molecular mechanism of the initiation of pathogenic aggregation of beta-amyloid two compounds capable of blocking the aggregation of beta-amyloid peptide were patented. The study of the properties of these compounds in animal models showed that they reduce the risk of developing a disease corresponding to Alzheimer's disease.
The staff of the Laboratory of Magnetic Tomography and Spectroscopy of Moscow State University carried out the research in collaboration with the scientific team of the Institute of Molecular Biology RAS. V.A. Engelhardt (IMB RAS) under the leadership of Academician Alexander Makarov. Researchers expect that the results of their work in the future will help in the development of compounds that can stop the development of Alzheimer's disease.