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New targets for drugs to slow down dementia

17 Jun 2015

Neurodegenerative diseases such as Alzheimer’s disease are horrible and incurable conditions that cause nerve cells to die. They’re strongly linked with ageing. As the proportion of elderly people in the European population continues to rise – it’s projected to reach 25 per cent by 2030 – neurodegenerative diseases are a huge problem for our society and the MRC is channelling considerable resources into tackling them.

In 2013, scientists from the MRC Toxicology Unit in Leicester led by Professor Giovanna Mallucci made a breakthrough which points to promising new targets for drugs to slow down the tragic decline into dementia which affects so many people and their families.

The research team had previously found a major pathway in the brain which leads to brain cell death in mice. So they then gave a chemical compound to block the pathway in mice with prion disease - and were delighted to find that it stopped the disease in its tracks, restoring some normal behaviours and preventing memory loss and all clinical signs of neurodegeneration.

“It was extraordinary,” says Giovanna, describing the moment she realised that it had worked. “It was absolutely clear that the treated animals were cured. Everyone involved, from the animal technicians to the researchers, was excited. It was so obvious which mice had had drug and which had had placebo. To have your hypothesis borne out by seeing animals that were so clearly not neurologically ill was really fantastic.”

In prion disease, and in Alzheimer’s and Parkinson’s diseases, brain cells produce misshapen proteins. The presence of these ‘wonky’ proteins kicks off a natural defence mechanism in brain cells, which temporarily switches off the production of all new proteins. This mechanism – known as the PERK pathway - normally switches back ‘on’ again, but in mice with prion disease the continued build-up of misshapen protein prevents this from happening. Because proteins which are critical for the brain cells’ survival stop being made, they die.

Giovanna’s team had previously injected a protein that blocked effects of activation of the PERK pathway into a small area of the brains of mice, and by doing this were able to restore protein production, and stop the brain cells from dying. This led them to predict that compounds able to block PERK would also protect brain cells.

Sure enough, when the team gave the mice a PERK-blocking compound, the drug was able to enter the brain from the bloodstream and stopped progression of the disease throughout the whole brain.

The compound, originally developed by GlaxoSmithKline as a possible cancer drug, is not fit to use in humans because it has serious side effects: it causes damage to the pancreas. But Giovanna’s research has clearly established the PERK pathway as a promising target.

Since their 2013 breakthrough, the team has repeated the experiment in mice using a different compound to target the PERK pathway, but at a later stage in the chain of events that leads to protein production in brain cells being switched off.

Giovanna explains: “This was very exciting because the compound we used in this experiment is less efficient at blocking the unfolded protein response, and we’ve found that if you partially restore protein synthesis you can both protect the brain from degeneration and prevent the toxicity to the pancreas which we saw in our earlier research.”

She adds that this compound isn’t suitable for use in people because it’s not soluble enough to be carried in the bloodstream, but the fact that it can protect the brain without harming the pancreas is important.

“The next step is that we have to absolutely understand the relevance of this pathway in human neurodegenerative disease. PERK pathway activation is seen in the brains of people with Alzheimer’s and Parkinson’s diseases. It’s also clear that brain cells need good rates of protein synthesis [protein-making] to survive, particularly after decades. And we know that repair processes are impaired as we age so I think boosting levels of protein synthesis is likely to be good for brain cells,” she says.

While she is cautious about revealing too much, Giovanna hints that there is already industry interest in her team’s work.

“Ultimately I hope this research will help us to prevent or slow down neurodegeneration. And you know I think a lot of people would settle for that. If you could prevent progression of disease that would already be an enormous step forward in preserving quality of life and preventing people from becoming institutionalised,” says Giovanna.

Further information:

Medical Research Council scientists discover compound that arrests neurodegeneration in mice

Read more about Giovanna's group's research


  • Categories: Research
  • Health categories: Neurological
  • Strategic objectives: Tissue disease and degeneration, Securing impact from medical research, Aim: Picking research that delivers
  • Locations: Leicester
  • Type: Success story