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In a new study conducted by the Sagol Department of Neurobiology at the University of Haifa and published recently in the Journal of Neuroscience, researchers report that they’ve found a way to improve memory by manipulating a specific molecule that is known to function poorly in old age and is closely linked to Alzheimer’s disease.
“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.”
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Insomnia increases the risk of Alzheimer’s disease – Research Finding
Young and middle-aged adults who suffer from insomnia and other sleep disorders may be more likely to develop Alzheimer’s in later life, research in mice suggests.
Insomnia may raise levels of amyloid beta in the brain. The protein is associated with Alzheimer’s disease. Photograph: Getty
Researchers monitored levels of amyloid beta, a protein fragment known to be linked to Alzheimer’s, in the brains of sleep-deprived mice with symptoms of the disease.
They found that preventing the mice from sleeping caused a 25% increase in amyloid beta levels. The peptide builds up in the brains of Alzheimer’s sufferers to form damaging plaques.
Amyloid beta levels were generally higher when mice were active than when they were sleeping, and animals that stayed awake longer had higher amounts of the peptide in their brains. The research will be published tomorrow in the journal Science.
Another study, also published in Science, links the finding to humans, showing that amyloid beta levels in the spinal fluid of volunteers increased when they were awake and fell during sleep.
Professor David Holtzman from the Barnes-Jewish Hospital in St Louis, US, where both studies were carried out, said: “The results suggest that we may need to prioritise treating sleep disorders not only for their many acute effects, but also for potential long-term impacts on brain health.”
The scientists also found a link with orexin, a protein involved in regulating the sleep cycle. When orexin was injected into the brains of mice, the animals stayed awake longer and levels of amyloid beta in their brains increased.
A drug that blocked the action of orexin led to a significant reduction in levels and increased the amount of sleep.
Three weeks of chronic sleep deprivation was enough to accelerate the deposition of amyloid plaque in the brains of the mice. But after two months of treatment with the orexin blocker, the deposits had shrunk by more than 80% in some cases.
“This suggests the possibility that a treatment like this could be tested to see if it could delay the onset of Alzheimer’s disease,” said Prof Holtzman.
He pointed out that as people age and their risk of Alzheimer’s increases, they usually sleep for shorter periods.
Further studies are being considered to see whether chronic sleep loss in young and middle-aged adults increases the risk of Alzheimer’s in later life.
Alzheimer’s is the most common form of dementia, affecting an estimated 700,000 people in the UK. The figure is expected to double within a generation.
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