Alzheimer's Mass spectrometry
Skoltech Group of Scientists under the guidance of Professor Evgeny Nikolaev, together with colleagues from MIPT, the V.A. Engelhardt Institute of Molecular Biology (IMB RAS) and the N.M. Emanuel Institute of Biochemical Physics (IBCF RAS), analyzed the possibilities of mass spectrometric methods for the study of a wide range of beta-amyloid peptides, which are among the main biomarkers of Alzheimer's disease. The journal Mass Spectrometry Reviews published an article in which scientists summarize the latest achievements in this field, and also report on the results of their research, where with the help of modern mass spectrometric methods they were able to detect a new potential trigger for accelerated formation of amyloid plaques in the cerebral cortex, which are considered one of the causes of Alzheimer's disease. New technologies based on mass spectrometry will help not only to better understand the pathogenesis of Alzheimer's disease, but also to learn how to diagnose it at an early stage, predict the risk of the disease and develop more effective therapeutic approaches.
Alzheimer's disease is the most socially significant neurodegenerative disease among the elderly and the main cause of dementia. Among the most characteristic neuropathological changes in Alzheimer's disease is the accumulation of beta-amyloid peptides in the cerebral cortex, which are fragments of the transmembrane precursor protein beta-amyloid, consisting of 39-42 amino acids and differing in length and biochemical properties. In addition, they have differences due to posttranslational modifications (PTM), i.e. changes in the chemical properties of amino acids that occur after protein synthesis. Scientists have found that individual PTMs contribute more than others to the formation of plaques and are present in high concentrations in senile plaques of patients with Alzheimer's disease.
By observing the whole variety of beta-amyloid peptides, it is possible to improve the accuracy of diagnosis and the effectiveness of monitoring the progression of the disease. The most accurate and reliable method of analyzing various types of peptides is mass spectrometry.
"We tried to demonstrate the possibilities of mass spectrometry for the study and diagnosis of Alzheimer's disease. In our review article, we presented not only the results of our own research, but also the achievements of other scientific groups in this direction," says Alexey Kononikhin, one of the authors of the article, a senior researcher at Skoltech. "Thanks to mass spectrometry, we have reached a new level in understanding the complexity of beta-amyloid peptides, which are present in a variety of isoforms throughout the human body. We have shown that in Alzheimer's disease, their composition changes, and by detecting individual isoforms of peptides, in particular, in a patient's blood sample, it is possible to diagnose Alzheimer's disease even at an early stage."
Mass spectrometry is an analytical method widely used for the analysis of peptides and proteins and allows obtaining information about the composition of a biological sample in the form of a mass spectrum, which shows the relative content of components with different masses, or, more precisely, different mass-to−charge ratios. Since amino acids differ in mass, an accurate measurement of the mass of the peptide and its fragments makes it possible to determine the amino acid sequence of the peptide and the presence of PTM.
"The use of mass spectrometry methods allowed us not only to detect beta-amyloid peptides in all their diversity, but also to get a more complete picture of what is happening. Mass spectrometry allows us to better understand the pathogenesis of Alzheimer's disease and more accurately diagnose this disease, especially in the early stages," continues Alexey Kononikhin.
Unlike conventional PTMs, amino acid isomerization, which is of particular importance in the case of Alzheimer's disease, does not lead to a change in the mass of the peptide, so it is not so easy to detect it. In the case of beta-amyloid peptides, spontaneous isomerization of the 7th amino acid in the sequence, the aspartic acid residue, is of particular interest. This modification is present in most plaques in patients with Alzheimer's disease and is considered a potential trigger for the accumulation of beta-amyloids.
"We have developed a quantitative mass spectrometric method for detecting isomerization and investigated the accumulation of peptide forms in dynamics. For the first time, we demonstrated a comparison of beta-amyloid peptides from brain tissue samples of patients with Alzheimer's disease and transgenic mice with symptoms close to Alzheimer's disease. We found that in transgenic mice, the degree of isomerization of beta-peptides in plaques increases with age, and the process of plaque formation in these mice has a very interesting dynamics: in particular, starting from the age of 7 months, the content of isomerized forms increases, and from the age of 10 months, the rapid formation of plaques occurs. Thus, our results partially confirm the hypothesis that isomerization can serve as a trigger for the formation of plaques, however, additional experimental studies are needed to finally confirm this hypothesis," Alexey Kononikhin notes in conclusion.
The scheme of the experiment and the results of the study: transgenic mice were used for analysis, in whose brains beta-amyloid plaques are formed, as in Alzheimer's patients. The degree of isomerization of beta-amyloid peptides (vertically) is determined by the intensity of the mass spectrometric signal (horizontally). The results obtained for the human brain (green dot) are consistent with the results obtained for the brains of transgenic mice (purple dots). Source: Alexey Kononikhin.
The results presented by the authors indicate that, in relation to plaque studies in patients with Alzheimer's disease, mass spectrometric methods with high sensitivity and specificity can become an effective tool for verifying the results obtained by other methods, as well as for searching for new types of beta-amyloid peptides. The analysis of the varieties of such peptides is of particular importance for clarifying the pathogenesis of Alzheimer's disease, predicting an increased risk of developing the disease and developing effective therapy.
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