Improving memory by suppressing a molecule that links aging to Alzheimer's disease

The researchers even succeeded, for the first time, in manipulating the molecule's operations without creating any cognitive impairment.

"We know that in Alzheimer's, this protein, known as PERK, doesn't function properly. Our success in manipulating its expression without causing any harm to the proper functioning of the brain paves the way for improving memory and perhaps even slowing the pathological development of diseases like Alzheimer's," said Prof. Kobi Rosenblum, who heads the lab in which the research was done.

Previous studies at the University of Haifa and other labs throughout the world had shown that the brain's process of formulating memory is linked to the synthesis of proteins; high rates of protein production will lead to a strong memory that is retained over the long term, while a slow rate of protein production leads to weak memories that are less likely to be impressed on a person's long-term memory and thus forgotten.

In the current study, the researchers, Dr. Hadile Ounallah-Saad and Dr. Vijendra Sharma, both of whom work in Prof. Rosenblum's lab at the Sagol Department of Neurobiology, sought to examine the activity of a protein called elF2 alpha, a protein that's known as the "spigot" or regulator that determines the pace of protein synthesis in the brain during memory formation.

From earlier studies the researchers knew that there are three main molecules that act on the protein and either make it work, or stop it from working. During the first stage they sought to determine the relative importance and the task of each one of the molecules that control the activity of efF2 alpha and as a result, the ability to create memories. After doing tests at the tissue and cell levels, the researchers discovered that the main molecule controlling the efF2 alpha's activity was the PERK molecule.

"The fact that we identified the PERK as the primary controller had particular significance," said Dr. Ounallah-Saad. "Firstly, of course, we had identified the dominant component. Secondly, from previous studies we already knew that in generative diseases like Alzheimer's, PERK performs deficiently. Third, PERK acts on various cells, including neurons, as a monitor and controller of metabolic stress. In other words, we found a molecule that has a major impact on the process of creating and formulating memory, and which we know performs deficiently in people with Alzheimer's disease."

During the second stage of the study, the researchers sought to examine whether they could manipulate this molecule in rats in a way that would improve memory. To do this they used two accepted methods, one using a drug called a small-molecule inhibitor and the other making a genetic change to the brain cells using a type of virus also used in gene therapy.

After paralyzing PERK's activity or reducing its expression through gene therapy (which was done with the help of Dr. Efrat Edry, of the University's Center for Gene Manipulation in the Brain), the researchers measured a 30% increase in the memory of either positive or negative experiences. The rats also demonstrated improved long-term memory and enhanced behavioral plasticity, becoming better able to "forget" a bad experience. In other words, on a behavioral level it was clear that manipulating PERK by either of two methods improved memory and cognitive abilities.

When the researchers examined the tissues on a cell and molecular level, the discovered that the steps they'd taken had indeed stopped the expression of PERK, which allowed the "spigot" -- the elF2 alpha protein -- to perform better and increase the pace of protein synthesis. Even more, there was a clear correlation between memory function and the degree to which PERK was suppressed; the more efficiently PERK was suppressed, the better the memory function.

But the researchers faced another problem. Previous studies that had manipulated PERK in general in genetically engineered animals led to fixated behavior. "The brain operates in a most sophisticated fashion, with each action closely linked to many other actions," said Dr. Ounallah-Saad. "In our study we succeeded in maintaining such control of the PERK that it didn't influence the retrieval of existing memories, or do anything other cognitive damage."

"With this study we proved that we are capable of strengthening the process of protein synthesis in the brain and of creating stronger memories that last a long time," said Prof. Rosenblum. "The moment we did this by manipulating a molecule that we know performs deficiently in people with Alzheimer's and is linked to the aging process, we have paved the way for the possible development of drugs that can slow the progress of incurable diseases like degenerative brain conditions, Alzheimer's chief among them."