Early diagnosis of Alzheimer's disease
Diagnose Alzheimer's as early as possible
LifeSciencesToday based on EPFL materials: Diagnosing Alzheimer's earlier rather than later
A distinctive feature of Alzheimer's disease is the appearance of plaques in the brain. Plaques are gradually formed by the aggregation of small proteins called beta-amyloid peptides. As a rule, Alzheimer's disease is diagnosed with great difficulty, when the plaques have already negatively affected cognitive abilities, for example, led to memory loss. In a large study led by specialists from the École polytechnique fédérale de Lausanne (EPFL), an international team of scientists from Harvard, Edinburgh and Ulm has found a way to detect beta-amyloid aggregation at an early stage, which can make the diagnosis and treatment of this neurodegenerative disease much more effective. The study was published in the journal Alzheimer's and Dementia (Rudinsky et al., Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint).
Alzheimer's disease – and a number of other diseases – begins when beta-amyloid peptides begin to aggregate, or stick together, in the brain, forming larger structures called oligomers (from the Greek oligos – insignificant, few). Oligomers, in turn, stick together into even larger structures – beta-amyloid plaques. The problem here is the poor knowledge of the molecular mechanisms leading to the adhesion of beta-amyloid into oligomers. Moreover, the structure of oligomers itself remains a subject of debate among scientists. The aim of this international project was to study what happens during aggregation, especially in the early stages of this process.
Using various analysis methods (for example, mass spectroscopy), the researchers identified specific points on beta-amyloid peptides in which a process called autocleavage takes place. Usually beta-amyloid peptides are cut by specialized enzymes, and this is part of the cell purification process. But in this case, beta-amyloids simply burst at strictly defined points along their structure without any enzymes.
The researchers found that the auto-cleavage of beta-amyloid peptides occurs at the early stages of aggregation. This process generates truncated fragments of beta-amyloids, which can then form complexes with normal intact beta-amyloid molecules. This leads to the formation of neurotoxic oligomers, which are believed to be the cause of early cognitive problems characteristic of Alzheimer's disease.
In addition, the auto-cleavage of beta-amyloid leads to the formation of a clearly reproducible structure, or "fragment signature", which means that it can be used for early detection of beta-amyloid aggregation.
The scientists screened the tissues of mice used as standard models of Alzheimer's disease, as well as tissues of the postmortem human brain and cerebrospinal fluid. The study showed that the process of auto-splitting is a very important clinical sign of Alzheimer's disease.
Finally, the researchers found that truncated peptides can be used to develop antibodies capable of identifying and binding such peptides. This will allow doctors to monitor the accumulation of beta-amyloid fragments or even make them targets of the patient's immune system.
"The study shows new beta-amyloid targets associated with early signs of oligomerization," says project leader Adrian Schmid. "This can help diagnose the preclinical stage of Alzheimer's disease, as well as identify factors predicting clinical deterioration and progression of severe dementia."
These findings raise our understanding of beta-amyloid aggregation to a new level and may be of great importance for the diagnosis of Alzheimer's disease and future methods of its treatment.
"Preclinical biomarkers of dementia can help identify individuals who benefit from early therapeutic intervention," adds Schmid. "In this way, it can improve the patient's quality of life while reducing the costs associated with long-term medical care."
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16.05.2016