Researchers at Tel Aviv University have revealed the cellular mechanism used by the beta-amyloid protein

The connection between an excess of beta-amyloid protein and Alzheimer's disease has long been proven, but a study published today in the journal Nature Neuroscience found that the protein has a role in the transmission of information even in a healthy brain, and that its deficiency is also dangerous

In a study published today in the online version of the scientific journal Nature Neuroscience, a team of researchers led by Dr. Ina Slutsky from the Department of Physiology and Pharmacology at the Sackler School of Medicine at Tel Aviv University succeeded in deciphering one of the mysteries surrounding Alzheimer's disease - the normal function of the beta protein -Amyloid.
So far, an excess of this protein has been associated with cognitive decline in Alzheimer's, but it turns out that this protein has an important physiological role in the healthy brain as well - it regulates the transmission of signals between the synapses in the hippocampus, the area of ​​the brain responsible for learning and memory.
The students leading the research are Efrat Abramov and Petah Dolev, together with Hila Fogel and Eyal Roff from the Department of Physiology and Pharmacology at the Sackler School of Medicine at Tel Aviv University, in collaboration with Josepha Ciktostu from the University of Melbourne in Australia.

According to Dr. Slutsky, the common reference to beta-amyloid was as a toxic protein. "Our research showed that it is more complex. It is known that an increase in the protein concentration leads to a decrease in the number of synapses and damage to the cellular process responsible for learning and memory (synaptic plasticity). Dr. Slutsky's group proved that this protein has an important physiological role in the transmission of information in neural networks. "To our surprise, we discovered that a significant decrease in protein concentration also damages the cellular process responsible for learning and memory. This means that an optimal concentration of beta-amyloid is required for the proper transfer and processing of information, while a reduced or increased amount of it disrupts the process."

Most of the studies that have examined the effect of the protein so far have used genetic methods to create transgenic mice in whose brain beta-amyloid is secreted in an increased form. These methods as a model for the disease have two problems - first, they do not allow studying the initial processes that cause the disease because the protein begins to accumulate from the beginning of the development period. Second, they are only relevant to one type of the disease - Alzheimer's with a family background that appears at a young age and is caused by genetic mutations. According to Dr. Slutsky, this type constitutes only about one percent of the total population of Alzheimer's patients.

Recent studies show that the common type of the disease, in which Alzheimer's appears at a late age and sporadically, may result from damage to the protein breakdown mechanism and not from its overproduction. Therefore, Dr. Slutsky chose to use a different approach, through which it was possible to understand the early processes, which are at the basis of the disease. Instead of breeding mice with a genetic defect that increases the production of beta-amyloid, the enzyme neprilysin, which participates in the breakdown of beta-amyloid, is inhibited.

"The study shows that inhibiting the activity of nephrilysin increases the amount of the protein, which actually causes an increase in synaptic and nerve activity in a short period of time, and not a decrease in its amount, as previous studies showed in long periods of time. Using scientific methods at the cutting edge of technology, including optical, molecular and electro-physiological methods, led to the same conclusion. Given the fact that nephrilysin activity decreases with age, an increase in the background activity of synapses may be an initial step that causes a decrease in memory and cognitive ability in cases of sporadic disease."
This finding links to a study in humans conducted by Prof. Beckner from Harvard University, which showed that there is a connection between the level of brain background activity and the size of the beta-amyloid clusters: in those areas where there was increased brain activity at the beginning of the disease, large beta-amyloid clusters later developed.

This is Dr. Slutsky's first project in the field of Alzheimer's. According to her, the project would not have been possible without a basic understanding of the physiology and biophysics of the nervous system. "Only an understanding of the physiological principles responsible for nerve activity, in parallel with the development of innovative methods, will lead to a real solution, which will prevent the development of pathological processes."

In summary, the conclusions of the study are:
1. Beta-amyloid has a physiological role in the transmission of signals in neural networks.
2. Too low a concentration of the protein damages the cellular mechanism responsible for learning and memory.
3. An increase in the background activity of neurons constitutes the initial stage that causes neuronal disorders in the disease.