Early days for 'memory restoring' molecule

“Scientists believe they may have discovered the secret of restoring lost memory,” the Daily Express has reported.

The claim is based on research in mice that has identified a molecule called miR-34c that appears to be involved in learning and memory. Through various tests researchers found that blocking the action of miR-34c improved learning in mice with both an Alzheimer's-like brain condition and in old mice that typically experience age-related memory problems. However, it did not “restore memories”, rather it improved the mice’s ability to learn from their environment.

This type of research in mice is valuable as human brain tissue is not always easy to obtain, and early tests of new treatments need to be carried out in animals before they can be tested in humans. However, there are differences between the species that mean that results in mice may not be representative of what would happen in humans. In particular, Alzheimer’s disease is a complex disease, and mouse models may not be fully representative of its complexity.

However, when analysing tissue samples from people with Alzheimer’s and healthy elderly people the researchers found that those with Alzheimer’s disease had increased levels of miR-34c in a region of the brain important to memory. This supports the theory that miR-34c could play a role in learning and memory in humans as well, although much more research will be needed to determine if this is the case.

Where did the story come from?

The study was carried out by researchers from the European Neuroscience Institute in Germany and other research centres in Germany, Switzerland, Brazil and the US. It was funded by the European Science Foundation, the ERA-Net Neuron Epitherapy Project, the Hans and Ilse Breuer Foundation, the Schramm Foundation and the German Research Foundation.

The study was published in the peer-reviewed European Molecular Biology Organization (EMBO) Journal.

The Daily Express reported on this study. Although its report does correctly state that the study was in mice, its suggestion that memories were “restored” by the experimental treatment is not strictly accurate. Rather than enabling the mice to recall lost memories the treatment improved their ability to learn a “cue” from their environment and avoid a painful stimulus (a small electrical shock). As yet, we do not know whether the approach tested in this study would be effective or safe for humans.

What kind of research was this?

This was animal and laboratory research looking at the presence and action of certain molecules in a region of the brain called the hippocampus. The researchers wanted to look at the hippocampus because this area of the brain is important in forming memories. It is reported to be one of the first brain regions affected by ageing and forms of dementia such as Alzheimer’s disease.

The researchers were interested in understanding the actions of types of molecules called microRNAs or miRNAs. These play a role in helping to control which genes are able to produce proteins. This study aimed to identify all of the miRNAs within the hippocampus, and identify those that are particularly abundant in this area of the brain, as these miRNAs might play a role related to the formation of memories.

This type of study is easier to perform in mice because of difficulties in obtaining suitable human brain tissue samples. Differences between the species mean that the results may not be directly applicable to humans. In this study the researchers tested whether the miRNAs they identified in mice were also found in brain tissue from humans with and without Alzheimer’s disease.

What did the research involve?

The researchers extracted all the very small RNA molecules from mouse hippocampus tissue, and determined their genetic sequence. They then compared the levels of the various miRNAs in the mouse hippocampi and brain tissue as a whole. They also looked at which miRNAs were present at the highest levels in the hippocampus.

The genetic sequence of each miRNA determines which genes it targets and helps to regulate. They looked at what genes the most abundant hippocampal miRNAs might target, and whether these genes were likely to be involved in nerve cell function. They also looked at whether the genes targeted by these miRNAs were switched on (or ‘activated’) in mice’s brains in response to a fear conditioning task, which involves learning to associate an environmental “cue” with an unpleasant stimulus (a mild electrical shock to the foot). If these genes became activated in response to this task it would suggest that they were involved in learning.

Through these tests the researchers identified a particular miRNA molecule called miR-34c that looked like it could be involved in regulating nerve cell function, and performed a number of tests focused on its actions. First they looked at its levels in the hippocampi of older mice (24 months old), which provide a model of age-related memory impairment. They also looked at its levels in mice genetically modified to develop amyloid deposits in their brains, similar to those seen in Alzheimer’s disease. They also looked at the level of miR-34c in brain tissue from postmortems of six people with Alzheimer’s disease and eight age-matched control individuals.

The researchers then looked at whether changing the levels of miR-34c in the brains of regular mice could influence their learning and memory. First, they injected mice with a molecule that acts like miR-34c, and looked at the effect on their learning in the fear conditioning task, and in two other behavioural tests, including a test of memory (the water maze test) and an object recognition task.

They also injected the brains of the Alzheimer’s mouse model and old mice with either a chemical that would block miR-34c or a control chemical, and looked at their performance in the fear conditioning task, memory test and object recognition task.

What were the basic results?

The researchers found that 23 known miRNAs were present at high levels in the hippocampus, accounting for 83% of the miRNAs identified.

There were similarities in the miRNAs found in mouse whole-brain tissue and those found in the hippocampus. However, some miRNAs that were only found at low levels in whole-brain tissue were present at high levels in the hippocampus, most notably miR-34c.

The miRNA miR-34c molecule was predicted to target genes involved in nerve cell function, and these genes were found to be switched on in mice’s brains after the fear conditioning task, supporting the theory that they might be involved in learning. The miRNA miR-34c was also found to be present at high levels in the hippocampus of older mice with age-related memory problems and a mouse model of Alzheimer’s disease.

Testing of human tissue samples showed that levels of miR-34c were higher in the hippocampi of people with Alzheimer’s disease than in age-matched controls.

Injecting mice’s brains with a molecule that acts like miR-34c impaired their ability to learn in the fear conditioning task, and their memory in the water maze and object recognition tasks.

Injecting the Alzheimer’s model mice with a chemical that would block miR-34c led to them showing similar performance in the fear conditioning task to similarly-aged normal mice. Injecting them with a control chemical had no effect, with the mice showing the expected problems with their memory. Similar results were seen in mice with memory problems due to old age.

How did the researchers interpret the results?

The researchers conclude that “miR-34c could be a marker for the onset of cognitive disturbances linked to [Alzheimer’s disease] and indicate that targeting miR-34c could be a suitable therapy”.

Conclusion

This research has identified a specific microRNA molecule that appears to be involved in learning and memory in mice. Blocking the action of this microRNA seems to improve learning in mouse models of Alzheimer’s disease and age-related memory loss.

This type of research in mice is valuable, as suitable human brain tissue is not easy to obtain, and early tests of new treatments need to be carried out in animals before they can be tested in humans. However, there are differences between the species that may mean that results in mice may not be representative of what would happen in humans. In particular, Alzheimer’s disease is a complex disease, and mouse models may not be fully representative of its complexity. Also, the delivery method used in the mice in this study – regular injections directly into the brain – would not be suitable for clinical use.

The researchers’ tests suggest that the miR-34c is present in human hippocampi, and at higher levels in those with Alzheimer’s disease than age-matched controls. This does support a potential role for the microRNA in humans as well, but much more research will be needed to determine if this is the case.

This future research could include the examination of further human tissue samples to verify differences between people with Alzheimer’s and healthy individuals. However, before any testing in live humans could be contemplated there would need to be a great deal more research in mouse models of Alzheimer’s disease, which would need to determine how blocking miR-34c might have an effect in learning and memory, and whether it has an effect on the progressive brain changes that occur in the disease. They will also determine whether blocking miR-34c results in long-lasting improvements in memory, and what effects it might have.

There is a need for new treatments for forms of dementia such as Alzheimer’s disease, so research into potential new treatments is important. However, developing new treatments is a long process, and not always guaranteed to be successful.