They may help to explain why decades of study into the causes of the disease have so far failed to lead to a cure.
Alzheimer’s disease is widely believed to be caused by the gradual accumulation in the brain of amyloid-beta peptide which is toxic to nerve cells. Amyloid beta peptide is formed from a protein known as APP, which is found in three forms. Most research into APP – a key area of study for the disease – does not distinguish between the different forms of the protein.
The findings, published in the Journal of Biological Chemistry, show that amyloid beta peptide is actually created mainly by just one form of APP – known as APP695 for the number of its amino acids. APP695 is found at greater concentration in brain and nerve cells, but this study – funded by the Medical Research Council and the Alzheimer’s Research Trust – is the first time the significance of that has been shown. This discovery will now enable research to focus more clearly on the exact mechanism by which amyloid beta peptide accumulates in the brain.
“Research into amyloid beta peptide has been going on for more than 20 years and while treatments have made it to clinical trials, nothing has proved truly effective against this disease,” says Professor Tony Turner, from Leeds’ Faculty of Biological Sciences, who co-led the research. “This could be because research to date has been a bit of a blunt instrument: scientists have essentially been working on too broad a field. Our findings will allow researchers to target their work much more precisely.”
The study of APP695 also led the scientists to identify a potential new factor in the development of Alzheimer’s. When APP is broken down, it forms another protein called AICD. The researchers discovered that AICD formed from APP695 switches on certain genes within nerve cells that may then damage the cell. The process is unique to nerve cells and AICD formed from the other forms of APP does not have this effect.
“AICD has been detected before, but because studies haven’t differentiated between the different forms of APP, there was no consensus on its role,” explains co-researcher Professor Nigel Hooper. “It seems likely that AICD formed from APP695 is a contributing factor in the deterioration in nerve and brain cells which leads to Alzheimer’s. This provides another avenue for research into a potential cure for the disease.”
Professor Chris Kennard, chair of the MRC Neurosciences and Mental Health Board, said: “This is the latest study from a long-term research collaboration to significantly further our understanding of neurodegenerative diseases, such as Alzheimer’s Disease. It forms part of a £4.1m investment by the MRC and is a shining example of where fundamental research, which unravels the complex biology of disease, can provide the building blocks for potential treatments in future.”
Dr Simon Ridley, Head of Research at the Alzheimer’s Research Trust, said: “This study gives us important new insight into the role of APP in Alzheimer’s disease, and could have significant implications for future research in this area. We must now build on these findings with more research, as this is the only way we will be able to find an effective treatment for dementia.”
Over 820,000 people in the UK live with dementia and one in three over 65s will die with some form of the disease. The Alzheimer’s Research Trust estimates that the annual cost to the UK economy is £23 billion.
Professors Nigel Hooper and Tony Turner are available for interview
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Notes to editors:
- The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a beta-secretase dependent pathway
Nikolai D. Belyaev, Katherine A.B. Kellett, Caroline Beckett, Natalia Z. Makova,
Timothy J. Revett, Natalia N. Nalivaeva, Nigel M. Hooper and Anthony J. Turner
The paper is online at http://www.jbc.org/cgi/doi/10.1074/jbc.M110.141390
- The research is part of a long-standing and productive collaboration between the research groups of Professors Tony Turner, and Nigel Hooper, who both hold chairs in biochemistry in the Faculty of Biological Sciences at Leeds.
- The Faculty of Biological Sciences at the University of Leeds is one of the largest in the UK, with over 150 academic staff and over 400 postdoctoral fellows and postgraduate students. The Faculty is ranked 4th in the UK (Nature Journal, 457 (2009) doi :10.1038/457013a) based on results of the 2008 Research Assessment Exercise (RAE). The RAE feedback noted that “virtually all outputs were assessed as being recognized internationally, with many (60%) being internationally excellent or world-leading” in quality. The Faculty’s research grant portfolio totals some £60M and funders include charities, research councils, the European Union and industry. www.fbs.leeds.ac.uk
- The 2008 Research Assessment Exercise showed the University of Leeds to be the UK’s eighth biggest research powerhouse. The University is one of the largest higher education institutions in the UK and a member of the Russell Group of research-intensive universities. The University’s vision is to secure a place among the world’s top 50 by 2015. www.leeds.ac.uk
- For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including the first antibiotic penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk
- The Alzheimer’s Research Trust is the UK’s leading dementia research charity. As research experts, we fund world-class pioneering scientists to find preventions, treatments and a cure for dementia. Our findings improve the lives of everyone affected by dementia now and in the future and we help people to understand dementia and the progress we are making.