University of Haifa: ‘Repairing’ brain protein formation improves memory

Impairment in Alzheimer’s identified; start-up to research drugs to delay onset of disease.

By JUDY SIEGEL-ITZKOVICH
An image of the human brain (photo credit: REUTERS)
An image of the human brain
(photo credit: REUTERS)
University of Haifa researchers studying the molecular and cellular mechanisms underlying learning and memory have found that “repairing” this activity led to an improvement in memory. They have established a start-up company on the basis of these findings to develop drugs that delaying the onset of cognitive symptoms such as those in Alzheimer’s disease.
The study directed by Prof. Kobi Rosenblum in the university’s Sagol department of neurobiology has just been published in the Journal of Neuroscience.
“We found that the nerve cells in the mouse models of Alzheimer’s face a type of metabolic stress.
When a cell faces such metabolic stress, it is logical that it will reduce its activity level to survive,” said research student Yifat Segev, who carried out the study with Dr. Iliana Barrera, colleagues from Rosenblum’s laboratory and researchers from the medical school at the University of Bergen in Norway. “The problem is that this stress is chronic and leads to impairment of cognitive functioning,” Segev continued.
In recent years, Alzheimer’s researchers have focused mainly on an attempt to fight the disease after it has erupted and on understanding its pathology. But it is wellknown that the disease develops in the brain for many years before the patients or those around them complain of symptoms. A previous study by Segev at the laboratory for research of molecular and cellular mechanisms found a connection between a genetic condition known to be a risk factor for sporadic Alzheimer’s (that afflicts more than 90 percent of Alzheimer’s patients in Israel and around the world) and premature aging as manifested in ongoing metabolic stress.
In the previous study, Segev found a connection between abnormal activity of the elF2 protein, which is known to regulate the formation of proteins needed for the creation of long-term memories, and mice that carried the human gene APOE4, which is known as a key risk factor for sporadic Alzheimer’s. In the present study, Segev and Barrera reach an even deeper understanding of the abnormality of the process and, in particular, finds that “repairing” the process improves the ability to create memories.
As in the first study, a group of young mice carrying the human gene APOE4 showed cognitive impairment on the behavioral level – in other words, they showed signs of damage on the level of spatial memory. A molecular examination showed that the protein elF2 had undergone phosphorylation (a phosphate group had been added to it, changing its action), leading to several processes, including elevated expression of the RNA on another protein, ATF4. This elevation delayed the expression of additional genes associated with the creation of long-term stable memory.
According to Segev, who is in the closing stages of her doctoral thesis, the measurements show that in several parameters mice expressing the risk factor for Alzheimer’s “age” metabolically at a relatively young age. “The abnormal activity in the regulation of the activity of the ATF4 probably causes the cell to ‘feel’ that is under stress, that is – overactive. A cell that is in stress reduces its activity in order to survive with the goal of restoring it to a normal condition after the stress passes. The problem is that in Alzheimer’s, the stress is probably chronic, and thus there is no return to normal activity,” Segev explained.
“In previous studies we showed that it is possible to improve longterm memory by regulating the course of the PKR protein and the eIF2 in models in young and healthy animals. Then we found a connection between eIF2 and cognitive impairment in the context of Alzheimer’s,” she said. “Now, we have not only deepened our understanding of these processes, but we have also managed to show that it is possible to cause a cognitive improvement in an Alzheimer’s model.”
“I hope that the new start-up we established on the basis of these findings will enable a drug to be found that can delay the onset of cognitive symptoms in dementia patients and in people with various cognitive impairments,” Rosenblum concluded.