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'Historic breakthrough' in Alzheimer's research

October 10, 2013, 8:04 pm BST

"Scientists have hailed an historic 'turning point' in the search for a medicine that could beat Alzheimer's disease," is the exciting news in The Independent. This headline comes from an early study of the effects of a new drug on mice with a type of neurodegenerative brain disease. The scientists infected the mice with a prion disease. Prion diseases cause a build-up of abnormal proteins in the brain. This causes brain cells to "switch off" the production of normal proteins. Without these normal proteins, the brain cells die, causing memory and behavioural problems. This build-up of abnormal proteins is a similar pattern to what occurs in humans with Alzheimer's disease, though there is no evidence that prions are associated with the condition. Researchers found that the new drug prevents this switch from turning from "on" to "off", stopping brain cell death. Encouragingly, mice treated with the drug did not develop the memory and behavioural symptoms of prion disease. This is the first time researchers have prevented brain cell death. Current drugs for Alzheimer's can only reduce the speed at which cell death occurs. An obvious limitation to the study was that it involved mice, not humans. Also, what works for prion diseases may not necessarily work for conditions such as Alzheimer's. The treated mice also suffered severe side effects, such as weight loss, which could be problematic in a human population. With these limitations in mind, these early results are very encouraging. However, the researchers are right to point out that it will be a long time before this drug has potential applications for humans with any of these conditions.   Where did the story come from? The study was carried out by researchers from the University of Leicester and the University of Nottingham, and was funded by the Medical Research Council, UK. It was published in the peer-reviewed medical journal, Science Translational Medicine. One of the researchers involved in the study is an employee and shareholder of GlaxoSmithKline, the company that holds the patent for the drug being studied. This potential conflict of interest was made clear in the study. Despite some overly optimistic headlines, the media has generally reported the story accurately, pointing out that any potential treatments for these brain diseases would be a long way in the future. The Independent's reporting of the study was particularly well done. It managed to achieve the delicate balancing act of explaining why the results of this study were so exciting, while at the same time making clear that it could be many years before we see any benefit in humans.   What kind of research was this? This was a laboratory study carried out in mice. It aimed to see if a drug could prevent brain cell death after abnormal proteins had stopped them producing the normal proteins necessary for survival.    What did the research involve? The researchers have been trying to work out which mechanisms are behind the brain cell death seen in prion diseases such as Creutzfeldt-Jacob disease (CJD). In prion diseases, it has been found that a build-up of abnormally shaped proteins causes brain cells to switch off making proteins. This leads to brain cell death. This study aimed to see if a new type of drug could stop the cells from switching off this process. Some of the chemicals involved in this process, which were seen in increased levels in the mice, are also seen in high levels in the brains of patients with Alzheimer's disease (AD), Parkinson's disease and motor neurone disease. It is hoped that the type of drug used in this study might also benefit these groups of patients. In their experiments, the researchers infected wild-type mice with the prion disease "scrapie" (a condition that normally only affects sheep and goats) when they were four weeks old. They split the mice into two groups. In the first group, they treated 20 mice with the oral drug twice a day and gave a placebo to nine mice seven weeks after they were infected. At this stage, there was clear evidence of infection in the brain, but they did not yet have the associated memory or behavioural problems. In the second group, treatment was started after nine weeks, when the mice had signs of memory and behavioural problems. The researchers gave the drug to nine mice and a placebo to eight mice. They also gave the drug to a different group of mice who had not been infected. Symptoms of scrapie, such as memory and behavioural problems, are usually seen within about 12 weeks after the initial infection has occurred.   What were the basic results? Twelve weeks after they had been infected, none of the 29 mice treated with the drug had any signs of scrapie disease, whereas all 17 controls were terminally sick. Some of the mice who had been treated had occasional early indicator signs, but none of them developed clinically significant scrapie by 12 weeks. In the second group of mice – who started treatment after symptoms had developed at nine weeks – the treatment did not restore object recognition memory. Object recognition memory is the ability to remember information about objects, such as shape and colour. In mice, this can be tested using a range of methods, such as training them to press a certain coloured button to release a pellet of food. But the drug did restore what is known as "burrowing ability". Burrowing ability is the natural instinct of many animals to dig a hole or tunnel to create a safe place for itself. If an animal loses this instinct, it can be a sign that they are experiencing behavioural problems. The drug did not have any effect on the amount of abnormal prion proteins that accumulated in the mouse brains, but there was no evidence that this caused the mice any problems. Long-term survival was not assessed, as this would have subjected both sets of mice to unnecessary cruelty. The terminally sick mice were sacrificed at 12 weeks. The treated mice lost more than 20% of their body weight, which meant they had to be culled in accordance with UK Home Office regulations. They also had elevated blood glucose levels, but below the diabetic range in mice.   How did the researchers interpret the results? The researchers concluded that the drug can halt the progression of prion disorders in mice, but that further development is essential before this knowledge can be used for humans. This would include making sure that the drug had no side effects, such as weight loss and increased glucose, but also looking at its effects over a much longer timescale. The researchers point out that if a form of this drug were used in humans, it might involve treatment for years, or even decades. This means that reducing the risk of serious complications or side effects is essential.   Conclusion This study showed an exciting new development in the quest for treating prion diseases, also known as transmissible spongiform encephalopathies (TSEs), such as Creutzfeldt-Jacob disease (CJD) in humans or bovine spongiform encephalopathy (BSE) in animals. This was a small study of 29 mice and had to be discontinued after 12 weeks. Despite encouraging results, including that after this time period the prion disease had not progressed and the drug had stopped brain cell death, we do not know how long the drug might work. The researchers also point out that in these early stages they have not worked out how to stop the drug from having adverse effects on other parts of the body, such as severe weight loss and on organs such as the pancreas, which could trigger the onset of diabetes in humans. The drug did not prevent the build-up of abnormal proteins in the brain. Although the mice receiving the drug did not appear to suffer from the symptoms of prion disease, it is not known what effect these abnormal proteins may have on the brain in humans long term. The researchers conclude that this may also be effective in other neurodegenerative diseases, such as Alzheimer's and Parkinson's, but this theory has not been tested. It is likely that this research will lead to further animal studies. There is also the possibility that the drug could be tested in "biological surrogates" for human tissue, such as nerve cells generated from stem cells. But even if the drug passes these sorts of tests with flying colours, it would probably be at least a decade before we would see phase I clinical trials in humans.   Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Links To The Headlines Alzheimer’s treatment breakthrough: British scientists pave way for simple pill to cure disease. The Independent, October 10 2013 Alzheimer's breakthrough hailed as 'turning point'. BBC News, October 10 2013 Alzheimer's drug 'turning point in history of disease'. The Daily Telegraph, October 9 2013 Could there be a cure for Alzheimer's in the next decade? Breakthrough as scientists manage to stop brain cells from dying. Daily Mail, October 9 2013 Alzheimer's Pill Hope After Breakthrough. Sky News, October 10 2013 Alzheimer's drug breakthrough: Scientists hail turning point in fight against brain diseases. Daily Mirror, October 9 2013 Cure for Alzheimer’s disease is ‘within reach’. The Times, October 10 2013 Links To Science Moreno JA, Halliday M, Molloy C, et al. Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice. Science Translational Medicine. Published online October 9 2013

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