Amyloid in vivo and in vitro
Beta-amyloids from the brain of people with Alzheimer's disease turned out to be unlike a laboratory analogue
Polina Loseva, N+1
Beta-amyloid filaments from the brains of patients with Alzheimer's disease turned out to be unlike the filaments that it forms in the laboratory. This was reported in the journal Nature Communications by a group of scientists who examined protein aggregates in an electron microscope (Kollmer et al., Cryo-EM structure and polymorphism of Aß amyloid fibrils purified from Alzheimer's brain tissue).
Unlike the laboratory analogue, the amyloid from the patients' brains is twisted not to the left, but to the right side, and takes not so many different forms. This means that the models that have been used so far to find a cure for the disease may not quite correspond to reality.
At the molecular level, Alzheimer's disease is caused by the aggregation of two proteins: beta-amyloid and tau protein. But if tau aggregates are also found in other diseases (for example, in the brains of Parkinson's patients), then accumulations of beta-amyloid are characteristic mainly of Alzheimer's disease. It is believed that these proteins lead to the death of nerve cells, but most often their aggregation is studied in vitro.
Marius Kollmer and his colleagues from Australia, Germany and the USA decided to characterize beta-amyloid aggregates in real brain tissue. To do this, they took tissue samples of the soft membranes of the brains of three patients who died of Alzheimer's disease.
Having examined the amyloid filaments in a transmission electron microscope, the researchers noticed that they have a spiral structure and resemble aggregates formed in vitro in shape, but they are twisted not to the left, but to the right side. In addition, the "real" filaments turned out to be more stable than their laboratory counterparts, and did not disintegrate under the action of protease enzymes.
Beta-amyloid filaments from patients' brains (upper row) and formed in laboratory conditions (lower row). A drawing from an article in Nature Communications.
The scientists also discovered using cryo-electron microscopy that the vast majority of the filaments they isolated from the patients' brains belong to three types of structure, depending on the thickness of the thread and the frequency of twisting of the spiral. Three types were equally found in all three samples, so they cannot be called patient-specific. At the same time, in previous in vitro studies, beta-amyloid took many different forms. This probably means that in real tissue, the spectrum of possible amyloid structures is highly limited or depends on a specific subtype of the disease.
Until now, the "amyloid hypothesis" has dominated among scientists who deal with Alzheimer's disease, according to which the cause of the disease is the accumulation of beta—amyloid, and the cure for it should destroy protein aggregates or interfere with their assembly. However, none of the drugs that the researchers created for this purpose showed efficacy in clinical trials.
The authors of the new work cautiously note that their data do not allow us to say unequivocally that amyloid forms completely different structures in vivo and in vitro, but indicate that laboratory models do not always accurately reflect reality. In fact, this means that, while developing means to combat beta-amyloid aggregates, scientists still did not have a very good idea of what their target looked like.
Previously, scientists have already proposed to consider Alzheimer's disease not a single disease, but a group of diseases, based on the structure of beta-amyloid. It has also been suggested that its aggregation serves to protect the brain from infections.
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