How to neutralize the "protein of forgetfulness"
Suppression of a molecule associated with aging and Alzheimer's disease strengthens memory
NanoNewsNet based on the materials of the University of Haifa:
Researchers find a way to improve memory by suppressing a molecule that links aging to Alzheimer’s diseaseIn a new study conducted at the Department of Neuroscience at the University of Haifa and recently published in The Journal of Neuroscience (Ounallah-Saad et al., Genetic or Pharmacological Reduction of PERK Enhances Cortical-Dependent Taste Learning), scientists have found a way to improve memory by manipulating a molecule closely related to Alzheimer's disease, whose function, in addition, it is broken in old age.
For the first time, researchers have succeeded in manipulating the activity of this molecule without causing any cognitive impairment.
"We know that in Alzheimer's disease, the function of this protein, known as PERK, is impaired. Our success in manipulating its expression without any negative effect on the functioning of the brain opens the way to improving memory and, perhaps, even slowing the development of pathology in diseases such as Alzheimer's disease," says Professor Kobi Rosenblum, who heads the laboratory in which this study was conducted.
Previous studies conducted at the University of Haifa and other laboratories around the world have shown that the process of memorizing information received in the brain is directly related to protein synthesis; high rates of protein production cause good memorization (information is stored for a long time), while low rates weaken the memorization process. The information obtained at a low level of protein synthesis is unlikely to be imprinted in long-term memory and, therefore, will be forgotten.
In this project, scientists studied the activity of the elF2alfa protein, a regulator that determines the rate of protein synthesis in the brain during the memorization process.
From previous work, the researchers knew that there are three main molecules acting on this protein and either forcing it to perform its function or blocking it. At the first stage, they decided to determine the relative importance and task of each of these molecules. After conducting experiments at the tissue and cellular levels, the researchers concluded that the main molecule controlling the activity of elF2alfa is the PERK protein molecule.
"The fact that we have identified PERK as the most important regulator is of particular importance," says Dr. Ounallah–Saad, an employee of Professor Rosenblum's laboratory. "First of all, of course, we have identified the dominant component. Secondly, we already knew from previous studies that in degenerative diseases such as Alzheimer's disease, PERK function is impaired. Thirdly, PERK acts in various cells, including neurons, as a control system and regulator of metabolic stress. In other words, we have found a molecule that has a huge impact on the process of memorization, the function of which, as we know, is impaired in people with Alzheimer's disease."
At the second stage of the study, scientists found out whether it is possible to control this molecule in rats in such a way as to improve memory. To do this, they used two well–known methods - low molecular weight inhibitors and the introduction of genetic changes in brain cells using a virus used in gene therapy.
After suppressing PERK activity or reducing its expression level through gene manipulation, the researchers found a 30% improvement in memory of both positive and negative experiences. In addition, the rats showed improved long-term memory and increased behavioral plasticity, becoming more able to "forget" negative experiences. In other words, on a behavioral level, it was clear that manipulating PERK with either of the two methods improved memory and cognitive abilities.
After studying the tissue at the cellular and molecular level, the researchers found that the steps they took actually stopped the expression of PERK, which allowed the regulator – the elF2alfa protein – to work better and increase the rate of protein synthesis. Moreover, there was an obvious correlation between memory and the degree of PERK suppression: the more PERK was suppressed, the better the memory was.
In previous experiments with the manipulation of the PERK protein, genetically engineered animals, as a rule, showed stereotypical behavior.
"The brain works in the most complex way, and each of its actions is closely related to many other actions," explains Dr. Unallah-Saad. "In our study, we managed to maintain such control over PERK that it did not affect the retrieval of existing information in memory and did not cause any other harm to cognitive functions."
"With this study, we proved that it is possible to enhance the process of protein synthesis in the brain and create more lasting memories that persist for a long time. At the moment when we did this by manipulating a molecule that is known to have impaired function in people with Alzheimer's disease and that it is associated with the aging process, we paved the way for the development of drugs that can slow the development of incurable diseases, such as degenerative brain diseases, the main among which is Alzheimer's disease." Professor Rosenblum commented on his work.
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