Turn your brain on: a "switch" of neural connections can help with Alzheimer's disease

Russian scientists have identified the properties of a protein that enhances calcium exchange between brain cells. Exposure to them strengthens neuronal connections, which means that it is capable of bringing back memory and thinking. The data obtained will help doctors to create a cure for Alzheimer's disease and other neurodegenerative diseases. To understand the mechanism of action of proteins experts were able to thanks to a new method of research: neurons were placed in a special gel and stretched them in different directions. This increased the cell almost three times and allowed to see what was previously unavailable to the microscope. According to experts, the discovery really brings specialists closer to creating new effective drugs. However, the path from the scientific stage to use on patients may take decades.

Protein that strengthens neuronal connections

Specialists from St. Petersburg's Peter the Great Polytechnic University have used modern methods to study the mechanism of calcium exchange in the cell culture of hippocampal neurons, the brain structure responsible for memory. They discovered a new mechanism that stimulates the formation of an accumulation of proteins - clusters that strengthen this process. As a result of their effects, neuronal connections that are responsible for memory and thinking are strengthened. Scientists also determined the function of one of the organelles of synapses of neurons, which was previously unknown. The data obtained could be used to create drugs against Alzheimer's disease and other pathologies associated with neurodegeneration.

- We were interested in the data of some studies on the action of clusters of one of the proteins in non-neuronal human cells. Researchers from the US and Europe have obtained results that clusters of type one proteins weaken the tubulin cytoskeleton (the skeleton of the cell), and hence calcium metabolism is reduced. However, there is a similarly structured type 2 protein that remains poorly understood - it is most commonly found in the synapses of mature neurons. Our data on neurons showed that thanks to the type 2 protein, the opposite is true - the effects of the cytoskeleton cause these proteins to form more clusters, which means calcium exchange is increased. To understand why the opposite results are obtained, we compared proteins from normal cells and from neurons. They are very similar to each other, but slightly different," said Ekaterina Pchitskaya, head of the Research Laboratory of Biomedical Image and Data Analysis at SPbPU.

Ekaterina Pchitskaya, Head of the Research Laboratory of Biomedical Image and Data Analysis at SPbPU

Photo: SPbPU

It turned out that despite the similarity in structure, these proteins are very different in action. In a cell model of Alzheimer's disease, the scientists showed that the neuronal protein strengthens synapses - intercellular communication between neurons. If you stimulate cluster formation with special structures of the cytoskeleton - microtubules - more calcium enters the cell, synapses become larger and the outgrowths themselves increase in size. They can resist toxicity and become more like normal cells, the researcher said.

Calcium exchange is important for all cells in the human body. In neuronal cells, signal transmission is impossible without it. Entering synapses, calcium triggers a cascade of reactions that lead to an increase or decrease in nerve spurs. In essence, neuronal change is the process of plasticity, that is, the transfer of information in the brain that enables memory and thinking. Without calcium exchange, this is impossible.

In their work, scientists used a new method of expansion microscopy, with which they saw what happens in cells with high magnification. The sample is placed in a special gel, then evenly stretched in different directions and magnified almost three times. This increases resolution without buying expensive equipment, allowing them to see things that were previously inaccessible on a standard microscope.

New targets for the treatment of Alzheimer's disease

Another important result of the research work is that scientists were able to show the effect of type II proteins on the endoplasmic reticulum (a poorly understood cell organelle) in neurons. It had previously remained unknown. It turned out that these proteins change its structure and stabilize neuronal communication. As a result, this connection can persist longer. With neurodegeneration, there is a lack of those very clusters in cells, which can lead to the absence of endoplasmic reticulum in synapses, and therefore make them less stable. The scientists are going to test this hypothesis in future studies.

Photo: SPbPU

- Since type II protein clusters are involved in the movement of the endoplasmic reticulum, they can be used as a new idea of targets for drugs against neurodegeneration," said Anastasia Rakovskaya, a research engineer at the Research Laboratory of Biomedical Image and Data Analysis at SPbPU.

In the future, the results of the study should help in the creation of drugs aimed at combating Alzheimer's disease and other neurodegenerative and cognitive disorders, including, possibly, Huntington's and Parkinson's diseases, said Stanislav Ottavnov, head of the Laboratory for Analysis of Population Health Indicators and Digitalization of Healthcare at MIPT.

Photo: SPbPU

- However, at the moment we have the results of laboratory research, and the creation of drugs based on them, and even more so their introduction into practice will take, unfortunately, more than a dozen years even at the current level of pharmaceuticals and biotechnology, - said Stanislav Ottavnov.

Dynamic microtubules are interconnected with dendritic spines forming neuronal connections. They play a critical role in maintaining normal neuronal function and synaptic transmission. The study of these interactions may help to better understand the mechanisms of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. This will make it possible to find new approaches to their treatment, added Olga Valaeva, head of the Virtual Clinic Research and Development Center at the Moscow Institute of Psychoanalysis.