Discovery of molecular pathway of Alzheimer's disease reveals new drug targets
21 November 2012
The discovery of the molecular pathway that drives the changes seen in the brains of people with Alzheimer’s disease is reported today, revealing new targets for drug discovery that could be exploited to combat the disease. The study gives the most detailed understanding yet of the complex processes leading to Alzheimer's.
Alzheimer's disease is associated with plaques made up of deposits between brain cells of a molecule called amyloid, which leads to the formation of tangles of twisted fibres made from a molecule called tau, found inside the brain cells. This causes the death of brain cells, which is thought to bring about the symptoms of memory loss and dementia. Although it has been accepted for over 20 years that the progression of disease is driven by amyloid and results in abnormal changes in tau, the exact mechanisms of disease remain something of a mystery.
Recent genome-wide association studies have identified the gene for a molecule called clusterin as a susceptibility factor for late-onset Alzheimer's disease. Levels of clusterin are also known to be elevated in blood in people with Alzheimer's from an early stage in the disease, so the researchers wanted to find out what role it might play in the progression of disease.
The team, led by researchers at King's College London's Institute of Psychiatry, looked first in mouse brain cells grown in the laboratory and found that the presence of amyloid alters the amount of clusterin in these cells. Clusterin then acts to switch on a signalling pathway that drives the changes in tau that are associated with the formation of tangles inside the cells, another hallmark of the disease. When this signalling pathway was chronically switched on in a mouse model of the disease, the researchers observed an increase in tangle formation and evidence of cognitive defects.
The study, published today in the journal 'Molecular Psychiatry', also looked in humans and detected the signature of clusterin activation in the brains of people with Alzheimer's but not in the brains of people with other forms of dementia.
Dr Richard Killick from the Institute of Psychiatry said: "This is the first time we've been able to connect the molecular mechanisms behind the formation of amyloid plaques in the brain with the formation of tangles inside the brain cells, two of the defining features of Alzheimer's disease. Our research has given the most detailed picture yet of how the disease progresses and we hope it will offer leads for the development of new treatments."
The signalling pathway that is turned on by clusterin is called DKK1-WNT. It involves interactions between a number of different molecules that could prove to be useful targets for the development of new drugs.
Current treatments for Alzheimer's are focused on alleviating the symptoms and there is no therapy that can prevent the progression of disease.
Professor Simon Lovestone, also from the Institute of Psychiatry, who led the study, said: "We have shown that we can block the toxic effects of amyloid when we stop this signalling pathway in brain cells grown in the lab. We believe that if we could block its activity in the brains of Alzheimer's patients too, we may have an opportunity to halt the disease in man. Indeed, we have already begun our own drug development programme to do just that and are at the stage where potential compounds are coming back to us for further testing."
The DKK1-WNT pathways has also been implicated in some human cancers and although there is no evidence for a direct link, the findings from this study mean that there could be an opportunity to make advances in Alzheimer's research by capitalising on knowledge that is being gained from cancer research, the authors suggest.
Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, which helped fund this study, said: "We will see more and more people affected by Alzheimer's disease as our population ages. This study gives us a much-needed additional insight to the complex biology that contributes to the development of Alzheimer's, which is vital if we are to develop new treatments that are so urgently needed."
The study was largely funded by the Wellcome Trust, the Alzheimer's Society, BUPA foundation and Alzheimer's Research UK.
Image: A region of amyloid plaque in the brain of a person with Alzheimer’s disease. Credit: Medical Microscopy sciences, Cardiff University/Wellcome Images
Senior Press Officer, Wellcome Trust
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Killick R et al. Clusterin regulates b-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Molecular Psychiatry 2012.
Notes to editors
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.
About King's College London
King’s College London is one of the top 30 universities in the world (2012/13 QS international world rankings), and was the Sunday Times University of the Year 2010/11, and is the fourth oldest university in England. A research-led university based in the heart of London, King's has more than 24 000 students (of whom more than 10 000 are graduate students) from nearly 140 countries, and more than 6100 employees. King's is in the second phase of a £1 billion redevelopment programme which is transforming its estate.
King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of the academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world-leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £525 million (year ending 31 July 2011).
King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar.
King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King’s Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services.
The College is in the midst of a five-year, £500 million fundraising campaign - World questions|King’s answers - created to address some of the most pressing challenges facing humanity as quickly as feasible. The campaign's three priority areas are neuroscience and mental health, leadership and society, and cancer.
About Alzheimer's Research UK
Alzheimer’s Research UK is the UK's leading charity specialising in finding preventions, treatments and a cure for dementia. To help defeat dementia, donate today online or by calling 01223 843899. Alzheimer's Research UK is currently supporting dementia research projects worth over £20 million in leading universities across the UK.
About the Alzheimer's Society
Alzheimer’s Society research shows that 800 000 people in the UK have a form of dementia, more than half of whom have Alzheimer's disease. In less than ten years a million people will be living with dementia. This will soar to 1.7 million people by 2051. The Alzheimer's Society works in England, Wales and Northern Ireland to champion the rights of people living with dementia and the millions of people who care for them. It also provides a National Dementia Helpline at 0300 222 11 22. To support people to live well today and fight for a world without dementia tomorrow, the Alzheimer's Society relies on voluntary donations. You can donate now online or by calling 0845 306 0898.