A new study at Tel Aviv University hypothesizes that disruption of high-frequency brain activity may cause Alzheimer's

The research published this week in the journal Nature Neuroscience won the prestigious grant of 2 million euros from the European Research Council (ERC)

As of today, there is no solution for Alzheimer's disease in the world. "For over a decade now, all attempts to create drugs to prevent memory deterioration have failed," says Dr. Ina Slutsky, head of the synaptic plasticity research group at Tel Aviv University's Faculty of Medicine and Segol School of Neuroscience. "The ground is definitely ripe for new directions in research, and I believe that the answers lie in basic processes that occur in the brain."

According to this concept, Dr. Slutsky's laboratory is engaged in basic research, and in 2009 discovered the physiological role of the amyloid-beta protein, which is the main component of the deposits that characterize the brains of Alzheimer's patients. Recently, the group revealed physiological mechanisms that regulate the molecular composition of amyloid-beta, which has significance in the development of the disease. The researchers believe that the new findings will make it possible to locate the initial disturbances that occur in the brains of people who will suffer from Alzheimer's - many years before the onset of cognitive decline.

The research, led by Dr. Ina Slutsky, was led by the post-doctoral student Yiftah Dolev and the research student Hila Vogel. The findings were recently published in the scientific journal
nature neuroscience.

Dr. Ina Slutsky's research proposal won a prestigious grant of two million euros from the ERC European Research Council.

World research to date

Until now, researchers around the world have focused on the study of familial Alzheimer's - a rare genetic disease but relatively accessible to research, which erupts already in the 40s of the patient's life. They managed to find out
About 150 genetic mutations cause the disease, most of which are concentrated in two proteins: APP (Amyloid Precursor Protein) - from which amyloid-beta proteins are formed; And presenilin (Presenilin) ​​– involved in the final cutting of the APP to form amyloid-beta. The search for a cure for the disease has focused mainly on ways to reduce toxic forms of the amyloid, but so far has not brought the hoped-for results.

Short amyloid, long amyloid

The common type of Alzheimer's is sporadic (random) Alzheimer's, which appears in old age and is responsible
For about 99% of the world's patient population. To find the causes of sporadic Alzheimer's, Dr. Slutsky chose to investigate the relationship between the activity of neural networks in the brain and the composition of the amyloid-beta formed in the brain cells.

"The amyloid-beta molecules produced in the brain appear in several sizes - from 39 to 43 amino acids," explains Dr. Slutsky. "Amyloid consisting of 40 amino acids (short) is the most common, while amyloid of 42 amino acids (long) is the one that tends to accumulate and form the deposits. About 100 of the mutations associated with familial Alzheimer's disrupt the balance between the two types of amyloid, in favor of the long amyloid. In most cases, they lead to an overproduction of long amyloids, but sometimes to a reduced production of short amyloids. The disruption of the balance is actually the cause of the onset of Alzheimer's disease. The big question is what causes the disruption in sporadic Alzheimer's patients - people who do not carry family mutations for the disease."

To find answers, the researchers in Dr. Slutsky's laboratory conducted a series of experiments. They sought to understand how the brain regulates the ratio of short to long amyloid, and to find out if the balance between the two types is affected by environmental factors and sensory experiences.

Yeftah Dolev examined the activity of the cells in the hippocampus of healthy rats - the same brain area associated with memory and learning, and affected by Alzheimer's disease. Yeftah gave the hippocampus slices electrical stimuli, which mimic the electrical activity that occurs in the brain as a result of environmental stimuli. As the amount of low-frequency stimulation increased, the production of amyloid-beta increased, but the ratio between the long molecules (42 amino acids) and the short ones (40 amino acids) did not change. "Then we tried to change the pattern of the electrical stimuli, and we got fascinating results," says Yeftah. "We gave the hippocampus network the same number of electrical stimuli, but this time the stimuli were arranged in short high-frequency clusters (bursts). The result was a significant increase in the amount of the short protein compared to the long one - that is, a process opposite to that occurring in Alzheimer's patients." It is important to note that it is already known that those groups of high frequency signals are very important in brain processes of information processing and encoding.

An examination of the synapses - the areas that connect the nerve cells in the brain and transmit information from one cell to another - revealed that their properties also probably have a part in the tendency to Alzheimer's. The researchers discovered that synapses that prioritize the transmission of high-frequency signals increase the amount of short amyloid compared to long. In other words: they create an effect opposite to that of familial mutations that cause Alzheimer's.

Presenilin lengthens and shortens

In the next step, the researchers looked at the mechanism that causes the change in the ratio between short and long amyloids. Researcher Hila Fogel focused on the presenilin protein, which determines the length of amyloid-beta proteins, and discovered that the structure of presenilin is sensitive to the pattern of electrical signal transmission. A burst of high-frequency signals changes the structure of presenilin, which moves to an open state - an effect opposite to that of the mutations that cause familial Alzheimer's, which move presenilin to a closed state. "For the first time, we showed that a non-genetic factor affects the structure of presenilin, and hence also the composition of amyloid-beta," says Hila. This is a significant finding in Alzheimer's research, which is an important step towards finding the causes of sporadic Alzheimer's, which affects millions of people around the world.

An environmental factor for Alzheimer's?

Can the brain phenomena revealed by research so far be due to environmental factors? In other words: Is it possible that the environment in which we live affects the development of Alzheimer's disease? To answer this question, the researchers chose to radically change the environment and the sensory experience of young, healthy rats, which are at a critical stage in their development. They placed the rats in dark cells, and tested the effect of the sensory deprivation on the properties of the synaptic filter, and hence on the ratio between the short and long amyloid. The surprising findings: the synapses in the hippocampus of the rats immersed in darkness preferred to transmit high-frequency signal bursts, which caused the production of more amyloid of the short type.

"For the first time, we showed that a sensory experience can affect the filtering of signals in the synapses in the hippocampus and the composition of amyloid-beta," concludes Dr. Slutsky. "Based on our findings, we hypothesize that it is possible that in old age changes occur in the pattern of signals and/or in the properties of synapses, which cause a decrease in the transmission of high-frequency signal bursts in the brain. This situation apparently results in a decrease in the short amyloid compared to the long, which ultimately causes the severe symptoms we know as Alzheimer's disease. To test our hypotheses, we are now starting a study in a mouse model of Alzheimer's, which will test whether it is possible to prevent the deterioration of memory by correcting the filter properties in the synapses of the hippocampus." This is basic research that may in the future lead to a breakthrough in applied research as well, looking for ways to diagnose, prevent and cure the disease.

Research students Hila Milstein and Neta Gazit and researcher Dr. Yevgeni Berdichevsky from Dr. Slutsky's laboratory, and Prof. Nils Bruce and Noa Lipstein from the Max-Planck Institute in Germany also participated in the study.