Final report: Unravelling the mystery of tau tangles Dr Amritpal Mudher, Southampton University

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1 Keeping you up to date March 2009 Final report: Unravelling the mystery of tau tangles Dr Amritpal Mudher, Southampton University Nerve cells in the brain produce many different proteins that ensure that the cells function correctly. The cell skeleton, or cytoskeleton, also plays a fundamental role. The cytoskeleton acts as a scaffold to maintain the shape of the nerve cell and provide tracks for the transport of molecules around the inside of the cell. Both of these functions are crucial for ensuring that nerve cells can communicate with each other. A nerve cell that loses contact with its neighbours will eventually die. Dr Mudher in her lab A hallmark of the development of Alzheimer s disease is the accumulation of toxic protein tangles in the brain, known as neurofibrillary tangles. The key component of these tangles is the tau protein, which is produced naturally by brain cells. In healthy cells tau is thought to play an essential role in helping to stabilise the cytoskeleton and keep the cellular transport system running smoothly. However, analysis of neurofibrillary tangles has revealed the presence of abnormal versions of In some, there are excessive amounts of one form of tau; in others the tau was modified far more than normal by the addition of extra phosphates to form hyperphosphorylated Dr Amritpal Mudher has shown that these abnormal tau proteins affect the stability and function of the cytoskeleton and could ultimately lead to the death of the nerve cell. In 2005 she was awarded a project grant to further investigate the mechanism involved and to determine how abnormal tau is produced. The research project is now complete. Dr Mudher s work, outlined below, continues to produce exciting and valuable results. Subsequently, her application for further funding to continue this study has been approved. Dr Mudher and her team at Southampton University work with fruit flies, which provide an excellent model for investigating the activity of nerve cells. It is very easy to engineer specific mutations in fruit fly genes, which lead to clear behavioural changes that are easy to measure. In addition, fruit fly larvae are transparent and so they are perfect for scientists to study the nerve cells inside them. Proteins of interest info@alzheimers.org.uk Website Registered charity no A company limited by guarantee and registered in England no

2 can be tagged with fluorescent markers and observed within the larvae. Dr Mudher has created a series of different fruit fly mutants whose nerve cells contain the various types of abnormal Dr Mudher proposed two potential mechanisms for how abnormal tau might affect the cytoskeleton and has used the fruit fly model to test these theories. She suggested that tau might interact with a kinesin, one of the cellular motors which drive transport around the cytoskeleton. The team used biochemical assays to confirm this interaction. This suggests that abnormal forms of tau could disrupt kinesin activity, potentially an important factor in understanding how tau tangles develop during Alzheimer s disease. The research will now progress to look at whether the interaction with k inesin changes in the presence of the abnormal hyperphosporylated An additional hypothesis was that abnormal tau might alter the structural integrity of the cytoskeleton itself. To investigate this, Dr Mudher s team used high-powered microscopes to study the state of the cytoskeleton in flies with either normal or abnormal tau, and to identify how tau was binding to it. Through the microscope: Fluorescent labelling of tau shows normal distribution of the protein in a healthy nerve cell This pattern of abnormal tau results in disruption of nerve cell shape and transport They found that in flies with hyper-phosphorylated tau, the cytoskeleton was fragmented and tau was not binding to it as efficiently as normal. This finding is key since it begins to explain why nerve cells become sick and die during development of Alzheimer s disease. To investigate how abnormal tau accumulates in the first place, Dr Mudher proposed a role for the well-characterised housekeeping system that controls protein production in all cells. This system involves a protein, GSK-3, which adds phosphates onto proteins and is known to be linked to the disruption caused by tau in nerve cells. It might therefore be involved in the production of the abnormal hyper-phosphorylated The research team found that chemicals that inhibit GSK-3 reduce tau production, thus implicating this important surveillance pathway in the accumulation of abnormal These lines of research explore the fundamental cause of Alzheimer s disease, investigating how and why the cytoskeleton of nerve cells breaks down, and the role of tau in this process. As the research progresses, Dr Mudher and her team hope that it will identify new targets for drugs designed to prevent the accumulation of tau and the formation of the toxic neurofibrillary tangles. Dr Mudher s findings have been very well received and have resulted in seven publications in high quality 2

3 journals. The work has also been presented as posters at a number of conferences and at numerous national and international meetings. Dr Mudher is a highly valued member of Alzheimer s Society s scientific community and we are delighted to be able to award her a new project grant for the continuation of her work, which is already underway. Research in the press Dr Anne Corbett, Alzheimer s Society Research Communications Officer Dr Anne Corbett Alzheimer s disease and dementia have received a great deal of coverage in the press in the past month. The launch of the National Dementia Strategy for England, as well as a number of high profile media stories, is helping to raise the profile of dementia in the public arena, and our press team have been kept very busy. The 17-point National Dementia Strategy includes the promise of a research summit to be held in summer of 2009 which will bring together major research funders to discuss how to progress dementia research in the UK. Following the announcement of the savings resulting from the National Dementia Strategy, Alzheimer's Society Chief Executive, Neil Hunt, called for balance in investment between research and care. He reasoned, It shouldn t be a choice between improving care and investing in research. We need to continue investing in both. Various studies have reported research into how lifestyle and long-term health impact on the likelihood of developing dementia. A new study published in the high profile British Medical Journal has added weight to the growing evidence that there is a link between passive smoking and dementia. Sarah Day, Head of Public Health at Alzheimer's Society, commented We ve known for some time that smoking increases your risk of developing dementia. It is important that smokers are supported to quit and the impact of second-hand smoke is reduced. Brain training products, which are marketed to reduce the risk of dementia, are becoming increasingly popular and sales are rising dramatically. However, Alzheimer s Society is concerned at the lack of evidence behind the manufacturer s claims. Use it or lose it is certainly a powerful public health message but it is too soon to say whether brain training can help in the battle against dementia, cautions Neil Hunt. New research into this issue is now starting to emerge, including a study in America that appeared to show some reduction in the risk of memory loss in adults who regularly read magazines, played games and took part in craft activities. However, more research, where people are followed up over time, is needed to understand whether these sorts of activities can reduce the risk of dementia, says Sarah Day. Scientists are continuing their search for ways to tackle accumulation of the toxic beta-amyloid protein. Research has shown that levels of the protein in the blood are linked to protein build-up in the brain. Professor Clive Ballard, Director of Research commented, This research suggests that by targeting levels of the amyloid in the blood stream we maybe able to regulate the levels of this toxic protein in the brain. 3

4 An interesting new study published in top journal Nature has identified a possible link between prions, which cause rare forms of dementia such as CJD and BSE, and betaamyloid accumulation. Professor Ballard said, This interesting study found the part of a prion protein that causes clusters of amyloid to form in the brain. More research is now needed to see if prion proteins could be a new target for Alzheimer s, or if they only play a part in prion dementias. Working in Partnership to prevent Vascular Dementia Sarah Day, Head of Public Health In May 2007, Alzheimer's Society hosted a joint workshop with Dementias and Neurodegenerative Diseases Research Network and the Stroke Research Network. This taskforce brought together leading researchers and funding organisations to establish the key research priorities for vascular dementia. The group agreed that there are excellent potential opportunities to prevent or delay the onset of dementia in people with existing cerebrovascular disease. However, at present the level of investment in this area lags substantially behind that of other common conditions affecting the brain. The taskforce discussion was distilled to identify the four highest research priorities in this area, with a particular focus on research that would lead to significant improvements in the treatment or prevention of vascular dementia within a realistic timeframe. The taskforce then nominated facilitators to lead workgroups responsible for developing specific research programmes. One of these groups, led by Philip Bath, has just been awarded joint funding by Alzheimer's Society and the Stroke Association. The group will test the feasibility of a clinical trial which would evaluate whether intensive treatment of blood pressure and/or cholesterol influences cognitive decline in people who have had a stroke. This is a particularly important outcome to investigate since it is estimated that 30 per cent of the one in six people who have a stroke go on to develop impaired memory and thinking, and then dementia. The taskforce approach appears to be a successful mechanism to galvanise research, particularly in areas which have received the least investment to date. Consequently, Alzheimer s Society is keen to fund further taskforces to stimulate similar advances in other areas. In particular, there is a need for more research to investigate whether nondrug related interventions for people with dementia can improve their quality of life. The desire to fund such clinical research is one of the unique features of the Alzheimer s Society research funding programme. QRD Liaison Officer David Buglar Telephone david.buglar@alzheimers.org.uk Scientific Liaison Officer Dr Ayesha Khan akhan@alzheimers.org.uk Head of Research Dr Susanne Sorensen Telephone ssorensen@alzheimers.org.uk 4

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