Reducing protein benefits memory in Alzheimer’s mice

The Journal of Clinical Investigation: Reducing ectopic expression of Ephexin5 ameliorates cognitive impairment in Alzheimer model

Researchers from the USA have identified a new protein that negatively regulates the growth of nerve cell connections, showing that reducing this protein in the brain increases the number of connections and improves memory and thinking in mice with features of Alzheimer’s. The study is published today (27 March) in The Journal of Clinical Investigation.

The researchers had previously identified a protein called ephexin5 that restricts the growth of nerve cell connections in early brain development. Once we are adults, the levels of this protein are lower and connections are constantly made and lost. However, the team found that in people with the early stages of Alzheimer’s, ephexin5 levels are raised suggesting that new connections may be prevented from growing. Nerve cell connections, called synapses, are crucial to the transmission of messages. Their loss is a key feature of Alzheimer’s, contributing to the changes in memory and thinking skills experienced by people with the disease.

To study how ephexin5 may be involved with changes at synapses in Alzheimer’s, the team investigated the effects of amyloid, the protein found built-up in the brains of people with Alzheimer’s. They saw that both in nerve cells in a dish and in mouse brains, amyloid caused an increase in the levels of ephexin5.

The researchers then bred mice that have features of Alzheimer’s disease, mice that do not have the ephexin5 protein, and mice with both features of Alzheimer’s and no ephexin5, to compare the differences in their brains and in their memory and learning skills. In the mice with features of Alzheimer’s, they found a reduced number of synapses and impaired memory and learning skills. In the mice with both features of Alzheimer’s and no exphexin5, they found that the number of synapses was similar to normal mice, and that the mice experienced no problems with memory and learning skills.

The results suggest that ephexin5 plays a key role in synapses and removing it may be a potential way to treat Alzheimer’s disease. To check that ephexin5 is involved with Alzheimer’s disease, the researchers used donated brain tissue to measure how much ephexin5 is in the brains of people with Alzheimer’s, compared with healthy older people. They found much greater levels of ephexin5 in the brains of people with Alzheimer’s disease, giving further support to the idea that this protein is linked with the disease process.

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said:

“The loss of connections between nerve cells is a key feature of Alzheimer’s, and one that is being increasingly recognised by those searching for potential new medicines for the disease. This study has revealed a new player controlling nerve cell communication that could be contributing to Alzheimer’s. These are important early steps along the road to new treatments for Alzheimer’s, and future studies will need to explore whether it is possible to safely reduce the levels of exphexin5 in the brain as an approach to help those living with Alzheimer’s. With 850,000 people in the UK living with dementia, it’s vital that research continues to develop effective new treatments for those affected and their families.”