Mass Spectrometry Could Enable Early Prediction of Alzheimer’s Disease from Blood Samples

Alzheimer’s disease (AD) is the leading cause of dementia and the most socially significant neurodegenerative disorder among the elderly. AD is characterized by the deposition of beta-amyloid (Aβ) peptides in the form of senile plaques. Although the mechanism of the disease is not yet fully understood, scientists believe that the formation of plaques is one of its causes. Mass spectrometry (MS) is an analytical technique widely used for the analysis of peptides and proteins. It provides information about a biological sample’s composition in the form of a mass spectrum, which reflects the relative abundance of components with different masses, or rather with different mass-to-charge ratios, to be precise. Now, research has confirmed that new MS-based technologies can help better understand the pathogenesis of AD, diagnose it at early stages, predict risks, and create more effective therapeutic approaches.

Scientists at the Skolkovo Institute of Science and Technology (Skoltech, Moscow, Russia) overviewed how MS techniques help to study the diversity of Aβ peptides, which are among the main biomarkers of Alzheimer’s disease. In their previous study using novel mass spectrometry methods, they had found a new potential trigger for the accelerated formation of amyloid plaques in the brain, which are considered to be one of the causes of AD. Aβ peptides are formed by cutting out chunks that are 39 to 42 amino acid residues long from the so-called amyloid precursor protein, which sits in the cell membrane. The resulting Aβ peptide isoforms vary in length and have different biochemical properties. Besides their length, the peptides also differ due to post-translational modifications, or PTMs. These are changes affecting the chemical properties of amino acids that occur after the protein has already been synthesized. It turns out that some ‌PTMs make for Aβ peptides that are especially prone to plaque formation - these are found in high concentrations in the senile plaques of AD patients.

Monitoring the diversity of Aβ peptides may help diagnose the disease more accurately and keep an eye on its progression. MS is the most accurate and precise way to analyze the various types of Aβ peptides. Since amino acids differ in mass, accurate measurements of peptide masses and those of their fragments make it possible to tell one Aβ peptide from another and even recognize PTMs. Unlike the usual PTMs, amino acid isomerization, which is of particular significance for AD, does not change a peptide’s mass and, therefore, its presence is trickier to detect.

In the case of Aβ peptides, spontaneous isomerization of the seventh amino acid in the sequence - the aspartate residue - is of special interest. This modification is often present in the plaques of AD patients and is considered a potential trigger for Aβ accumulation. The results of the latest study by the group of Skoltech scientists demonstrate that mass spectrometric studies of AD plaques can become an effective tool with high sensitivity and specificity, suitable both for validating the results obtained by other methods and for discovering new forms of Aβ peptides. Analyzing how their content varies is of particular importance for elucidating the pathogenesis of AD, predicting the risk of its onset, and developing effective therapy.

“Mass spectrometry allowed us to reach a new level of understanding of the complexity of beta-amyloid peptides, which occur in a great variety of isoforms throughout the body,” explained Alexey Kononikhin, Skoltech Senior Research Scientist. “We showed that their composition changes in Alzheimer’s disease, and detecting some isoforms of peptides - for example, in a patient’s blood sample - can even enable early prediction of AD.”

“Thanks to mass spectrometry, the diversity of various forms of these peptides has been confirmed. This expands our understanding and vision of what is happening: We see not just lots of Aβ peptides, but a whole complex picture. The method works well not only for understanding the pathogenesis of Alzheimer’s but also for better diagnostics, especially at early stages,” Kononikhin added. “We developed a quantitative mass spectrometric method for isomerization detection and studied the dynamic accumulation of peptide forms. We have compared for the first time beta-amyloid peptides from human AD brain tissue and transgenic mice with AD-like symptoms. We saw that the degree of Aβ peptide isomerization in plaques increased with mouse age. And the dynamics of this accumulation is quite interesting. For example, from the seventh month, the content of the isomerized form increases, and starting from 10 months of age, the plaques themselves form rapidly. Thus our findings confirm in part the hypothesis that isomerization may act as a trigger for plaque formation, but further experimental evidence is needed.”

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