Protein provides Alzheimer's clue

A gene therapy technique designed to ease the memory problems of Alzheimer's disease has been tested in rats, BBC News has reported. The website says that scientists took rats bred to have an Alzheimer’s-like condition and improved their memory problems by increasing levels of a chemical that helps brain cells signal to each other.

The laboratory study in question has detailed some of the complex pathways that underpin the nerve cell damage that is linked with Alzheimer’s disease. The researchers found that the protein deposits commonly found in the brain of people with the disease specifically affect the passage of nerve impulses through some brain cells. This, they discovered, is because the protein deposits interfere with a chemical that affects some important receptors in the brain.

This is a new line of research that may one day reveal a target for human treatment, but for now its direct relevance to human health is unclear. While the research has successfully tested a new ‘treatment’ in rats, it is not yet clear how they will be affected in the long term or how the treatment might translate to one that will be safe for use in humans.

Where did the story come from?

The study was carried out by researchers in San Francisco and was funded by the US National Institutes of Health. It was published in the peer-reviewed scientific journal Nature.

BBC News discusses the context and methods of this research well, and quotes relevant experts who have commented on what this study adds to this field.

What kind of research was this?

This was animal and laboratory research investigating the complex processes that underpin the decline in brain cell function that is associated with Alzheimer’s disease. The learning and memory deficits that accompany Alzheimer’s have been associated with fibre deposits in the brain called ‘amyloid-beta oligomers’. Mutant rats with high levels of these oligomers also have reduced levels of other key substances required for brain signalling (the passing of messages along nerves). In particular, there is evidence that a particular pathway called NMDA signalling is reduced. The NMDA pathway relies on an enzyme called EphB2, and when levels of this enzyme are reduced signalling through this pathway is dysfunctional.

In this study, the researchers were investigating whether amyloid-beta oligomers interfere with NMDA signalling, and specifically whether they affect levels of the EphB2 enzyme in rat brains.

What did the research involve?

There were several complex steps in this research. The researchers investigated the effect of oligomer fibres on EphB2 and then the effects of EphB2 depletion on cells, specifically on the signalling of brain cells in rats.

Researchers first investigated whether amyloid-beta oligomers could bind with EphB2 and the exact site at which the molecules bound. Having established this, they measured the levels of EphB2 in mutant rat brains at 2 months and 3-4 months of age to see at what age changes in EphB2 affected rats with an Alzheimer’s-like condition. They conducted further experiments on cultures of rat brain cells to determine exactly what effect the oligomers were having on the levels of EphB2 in the cells, and to identify any substances that might block this depletion.

The researchers then took rats that had an Alzheimer’s-like disease and attempted to ‘treat’ them using a gene therapy. To do this they used a virus vector to provide the rats with a gene that would increase their EphB2 levels. Behavioural experiments were conducted in Alzheimer’s rats treated with this gene to see whether it could improve their cognition.

What were the basic results?

The researchers found that the EphB2 enzyme could bind with the amyloid-beta oligomer fibres associated with Alzheimer’s disease. In rats with an Alzheimer’s-like disease, levels of EphB2 were lower than in control rats at 3-4 months, but not at 2 months. Treating cultured brain cells of normal rats with amyloid-beta oligomers for three days led their levels of EphB2 to become depleted. This depletion was found to be occurring within a structure in the cell called the proteasome.

The researchers also showed that a lack of EphB2 in the cell affected the NMDA signalling pathway, specifically reducing the way that signals passed through synapses along these nerve cells. This was because depletion of the EphB2 enzyme impaired the cell receptors involved in NMDA.

In live rats with an Alzheimer’s-like condition, the introduction of a gene to increase EphB2 levels performed as intended. These treated rats did not show the expected problems within their brain cells, which were now able to conduct impulses as normal. Testing showed the strength of the synapses involved in NMDA signals had been restored.

Rats treated to restore EphB2 levels also performed better on some behavioural tests – those involving spatial and nonspatial learning and memory. There was no improvement in tasks relating to other areas of the brain.

How did the researchers interpret the results?

The researchers conclude that depletion of EphB2 is important in “amyloid-b-induced neuronal dysfunction” and that increasing EphB2 levels or function could be beneficial in Alzheimer’s disease.

Conclusion

This is another well-conducted and well-described study conducted in rat cells in the laboratory. It is a complex study using methods that are appropriate in this field. That said, it is difficult to see the direct relevance of this research to humans. As with all animal research, it paves the way for similar research into human cells, and the findings of such future studies will have greater relevance for human Alzheimer’s. There are a number of ethical and technical issues associated with gene therapy in humans and a possible area for future research may be whether levels of EphB2 could be raised through other means.

One notable issue raised by the researchers is that this study has identified the involvement of EphB2 in only certain regions of the brain. Further research will be needed to determine whether the enzyme is also linked to the effects of Alzheimer’s seen in other parts of the brain. They say that if this is the case then EphB2 may be a target for drug treatments.