Beta-amyloid in high resolution

Scientists have "seen" the structure of beta-amyloid fibrils with high accuracy

Daria Spasskaya, N+1

A group of German scientists has published the structure of the amyloid fibrillation, consisting of β-amyloid, the main component of amyloid plaques responsible for the pathogenesis of Alzheimer's disease. The structure of the fibrillae was obtained using cryoelectronic microscopy and differs from previous similar structures in high resolution. For example, using these data, the researchers were able to predict the effect of several familial mutations associated with Alzheimer's disease. The article was published in Science.

Alzheimer's disease is a severe neurodegenerative disease accompanied by impaired cognitive functions. More than five percent of the population over 60 in developed countries suffers from it, and among people over 90 years old, the proportion of patients reaches 25 percent. Clusters called amyloid plaques are observed in the brains of sick people, which cause the death of neurons. These plaques consist of amyloid fibrils formed by a protein called β-amyloid.

This short protein consists of about forty (the amount may vary) amino acids and is formed as a result of "slicing" a large precursor protein. At a high concentration in solution, β-amyloid forms strong structures that stack up and form protofilament filaments. The latter "weave" one around the other with the formation of amyloid fibrils. A similar process occurs in the brain during the development of the disease. An idea of how a fibrillum is formed and its knowledge of its structure can give a lot of information about the pathogenesis of the disease.

Scientists have already managed to obtain structures of amyloid fibrils, but in a new work, researchers have managed to develop a way to "grow" fibrils of very good quality. Thanks to this, the authors obtained a structure with a resolution of four angstroms (0.4 nanometers), in which it is possible to "consider" the interaction of all amino acids composing the fibril. This made it possible to explain the already known data on mutant forms of β-amyloid, which tend to form fibrils with a greater or lesser degree.

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For example, rats and mice do not have Alzheimer's disease in nature, and this is due to the β-amyloid sequence. As the authors of the work have shown, a salt bridge between the glutamate residue at position 11 and histidine at position 13 is involved in the formation of amyloid structures by human protein. However, in mice, histidine in this position is replaced by arginine. Apparently, this is one of the reasons why the mouse protein does not form amyloid structures.

The authors of the work showed, using their model, that amyloid proteins with known "family" mutations, which were found in families with hereditary forms of Alzheimer's disease, should form fibrils very well. And β-amyloid with the "Icelandic" mutation, the carrier of which is one percent of the population of Iceland, based on the model data, forms fibrils poorly. Data on all these mutations were obtained experimentally by studying the behavior of proteins in solution, but the new structure will allow us to predict the effect of mutations, even without resorting to biochemical experiments.

Normally, β-amyloid does not form fibrils, however, its real functions in the brain are not entirely clear. There is a hypothesis that the formation of amyloid structures is necessary to protect the brain from infection, and Alzheimer's disease is the result of too acute a reaction. To prove this hypothesis, scientists have recently discovered pathogenic bacteria in the brains of patients. Researchers who deal with human evolution claim that the genes of "harmful" amyloid proteins are a "payment for intelligence" and got to us along with the genes that determine the development of the brain.

Portal "Eternal youth" http://vechnayamolodost.ru  12.09.2017