From: Andy Soos, ENN
Published June 17, 2013 08:35 AM

Memory Loss and Gain

Would it not be nice to take a pill and regain that elusive memory? We are all forgetful at times and without a clue as to how to get it better. Memory improved in mice injected with a small, drug-like molecule discovered by UCSF San Francisco researchers studying how cells respond to biological stress. The same biochemical pathway the molecule acts on might one day be targeted in humans to improve memory, according to the senior author of the study, Peter Walter, PhD, UCSF professor of biochemistry and biophysics and a Howard Hughes Investigator.

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The discovery of the molecule and the results of the subsequent memory tests in mice are published in eLife, an online scientific open-access journal, on May 28, 2013.

Memory is the process in which information is encoded, stored, and retrieved. Encoding allows information that is from the outside world to reach our senses in the forms of chemical and physical stimuli. In this first stage we must change the information so that we may put the memory into the encoding process. Storage is the second memory stage or process. This entails that we maintain information over periods of time. Finally the third process is the retrieval of information that we have stored. We must locate it and return it to our consciousness. Some retrieval attempts may be effortless due to the type of information.

One of the key concerns of older adults is the experience of memory loss, especially as it is one of the hallmark symptoms of Alzheimer's disease. However, memory loss is qualitatively different in normal aging from the kind of memory loss associated with a diagnosis of Alzheimer's. Research has revealed that individuals’ performance on memory tasks that rely on frontal regions declines with age. Older adults tend to exhibit deficits on tasks that involve knowing the temporal order in which they learned information; source memory tasks that require them to remember the specific circumstances or context in which they learned information; and prospective memory tasks that involve remembering to perform an act at a future time.

In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections.

The mice that received the chemical also better remembered cues associated with unpleasant stimuli — the sort of fear conditioning that could help a mouse avoid being preyed upon.

"It appears that the process of evolution has not optimized memory consolidation; otherwise I don't think we could have improved upon it the way we did in our study with normal, healthy mice," Walter said.

However, UCSF postdoctoral fellow Carmela Sidrauski, PhD, discovered that the chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what's known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha.

Scientists have known that in organisms ranging in complexity from yeast to humans different kinds of cellular stress—a backlog of unfolded proteins, DNA-damaging UV light, a shortage of the amino acid building blocks needed to make protein, viral infection, iron deficiency—trigger different enzymes to act downstream to switch off eIF2 alpha.

"Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation," Walter said, perhaps an evolutionary consequence of a cell or organism becoming better able to adapt in other ways.

Turning off eIF2 alpha dials down production of most proteins, some of which may be needed for memory formation, Walter said. But eIF2 alpha inactivation also ramps up production of a few key proteins that help cells cope with stress.

Study co-author Nahum Sonenberg, PhD, of McGill University previously linked memory and eIF2 alpha in genetic studies of mice, and his lab group also conducted the memory tests for the current study.

The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. 

"ISRIB shows good pharmacokinetic properties [how a drug is absorbed, distributed and eliminated], readily crosses the blood-brain barrier, and exhibits no overt toxicity in mice, which makes it very useful for studies in mice," Walter said. These properties also indicate that ISRIB might serve as a good starting point for human drug development, according to Walter.

Walter said he is looking for scientists to collaborate with in new studies of cognition and memory in mouse models of neurodegenerative diseases and aging, using ISRIB or related molecules.

For further information see Memory Loss.

Brain image via Wikipedia.

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