Features

In Alzheimer's disease, two proteins are known to accumulate and build up in the brain. One protein called amyloid β aggregates into large disruptive ‘plaques’, while tau protein forms tangled fibres within nerve cells.

Research has tended to focus on amyloid β, since small numbers of these proteins bound together are known to be toxic to the neurons in the brain.

But there is some evidence to suggest tau protein may also be involved in the processes which eventually lead to the memory problems and cognitive decline seen in Alzheimer’s.

Researchers at Oxford University have used a sensitive laboratory model of learning and memory to investigate any connection between amyloid β and tau. They found that tau is absolutely required for amyloid β to disrupt the function of the mouse nerve cells in the lab model. The results were published last month in the Journal of Neuroscience.

‘This is one of the first investigations of the mechanisms linking amyloid β and tau that is relevant to the early stages of Alzheimer’s disease,’ says Dr Mariana Vargas-Caballero of the Department of Physiology, Anatomy and Genetics, who led the work.

Mariana and colleagues looked at the strengthening of connections between mouse neurons in a dish, since the strengthening of connections in the brain’s neural circuits is thought to be how memories are formed and consolidated.

They found that amyloid β impairs the strengthening of the neural connections, or ‘synaptic plasticity’, although the nerve cells remained healthy in all other aspects that they could measure. But crucially, in neurons from mice engineered to have no tau protein, the amyloid β had no effect on this cellular model of memory.

‘This came as a complete surprise. It is a strong and reproducible effect,’ says Olivia Shipton of the Department of Physiology, Anatomy and Genetics, who is first author on the paper.

The team then went on to show that blocking the activity of tau using a specific chemical inhibitor also prevented the detrimental effects of amyloid β on the mouse neurons.

While it might be tempting to leap to the conclusion that this inhibitor could offer a promising avenue for the development of drugs to slow or halt Alzheimer’s onset, Mariana is more cautious. She says the stage the research is at is more about understanding the disease processes of early Alzheimer’s.

‘We want to know how amyloid β can lead to impaired synaptic plasticity as we can assume that this is like what happens in early Alzheimer’s disease. The findings should help us unravel the mechanism involved,’ she explains.

‘There is a huge gap in understanding what is relevant to the situation in humans. But we do now have a sensitive system to study what links amyloid β and tau, and tau and dysfunction in neural connections.

‘It is possible that pinpointing where in the chain of events tau is located could allow people in time to develop drug candidates to slow or stop the disruption of neural connections,’ she adds, but believes that more research is required to first understand the molecular pathways involving tau.

Mariana Vargas-Caballero is a Postdoctoral Training Fellow and Olivia Shipton is a DPhil student, both funded by the Wellcome Trust OXION initiative.

A novel way of finding people to take part in a new study of dementia is being employed by researchers from the universities of Oxford and London.

The Oxford Project to Investigate Memory and Ageing (OPTIMA) and the Centre for Stroke and Dementia Research at St Georges, University of London, will host stands at the Who Do You Think You Are? LIVE show, which starts 25 February at Olympia, London, where people interested in their ancestry will be enjoying ‘a weekend of discovery.’

The scientists are studying links between written language and dementia and looking for collections of text written by people with and without dementia.

They hope to make copies from diaries, letters, articles and books, written by the same person and ideally spanning three decades, to assess changes in the use of language by an individual and any links with the development of dementia. Changes detected could help diagnose Alzheimer’s disease earlier.

‘The types of people at the event are likely to be those who would keep records of their family history, family letters or journals,’ says Dr Celeste de Jager, Senior Research Associate in Neuropsychology at OPTIMA which is based at Oxford University’s Nuffield Department of Clinical Medicine

‘We want to interest people in the study because we need another 75 participants, each with a series of texts, to reach our target of 100.’ Dr Peter Garrard from St Georges is seeking a further 100 people for the same exercise. All copied text will be kept confidential and anonymous.

‘It isn’t the handwriting as such that’s important but the complexity of the text and use of language,’ Dr de Jager says. Deterioration in language is a common feature of Alzheimer’s disease and other forms of dementia. Loss of vocabulary and problems finding the right word are typical symptoms.

Writing samples for the study can be written or typed and must be from people of sixty years or older.

‘We will be looking for linguistic changes over time so need the same type of text from each person to have consistency,’ Dr de Jager says.

One person in five shows signs of dementia by the age of 80. Subtle problems may become apparent in spoken and written language before other symptoms such as memory loss are detected.

A trek to Everest base camp is helping Oxford University researchers investigate the links between heart failure and the low oxygen levels suffered by patients with a range of serious diseases.

Dr Cameron Holloway, Dr Nick Knight and Dr Andrew Murray from Oxford University's Department of Physiology, Anatomy and Genetics and the Oxford Centre for Clinical Magnetic Resonance Research were among several hundred volunteer hikers walking to the foot of Mount Everest to study the body’s response to the thin air.

The team wanted to simulate the condition of hypoxia – when the body or part of the body is deprived of sufficient oxygen. Patients with pneumonia, smoking-related diseases and some forms of heart failure suffer hypoxia.

It was Dr Holloway’s first experience of such a severe climate and he was startled by some of the findings. Among the most significant were changes to blood oxygen levels and energy synthesis.

‘I was amazed at how low the arterial oxygen levels fell in our blood,’ Dr Holloway said. ‘Saturation was in the 70 and 80 per cents during simple exercise at altitude when normally you would get worried if it dropped from normal at 98 per cent to 93 per cent.'

‘Usually that level isn’t compatible with life. If someone came in with levels that low we would rush them into intensive care.’

Another ‘huge shock’ was the 25 per cent drop in the cardiac phosocreatine/adenosine-triphosphate (PCr/ATP) ratio – a measure of the amount of energy available to the heart.

‘People with heart disease often have this ratio impaired. We experienced similar impairment, even reaching the levels of heart failure. We don’t know if it was due to adaptation to low oxygen or showed that our hearts were not coping.’

Dr Holloway’s study of 14 of the volunteers ran alongside a larger research project by Caudwell Xtreme Everest, part of the UCL Centre for Altitude, Space and Extreme environment medicine (CASE). The findings were published recently in The FASEB Journal.

Before leaving for Nepal, participants underwent wide-ranging tests, including assessments of heart, vascular, brain and exercise performance. Blood and other tests were carried out at several points during the 11-day ascent from Lukla’s Tenzing-Hilary Airport at 2,850m to 5,360m base camp.

The initial tests, which took place in Oxford, were repeated within 48 hours of the group’s return from Everest and carried out again six months after the trek ended. By then all changes to the heart and energy levels had returned to the pre-trek baseline.

Dr Holloway suspects that the findings witnessed during the Everest trip may have parallels with the cause of some forms of heart failure:

‘At base camp the symptoms we had, including breathlessness and exercise intolerance, were similar to those experienced by heart failure patients.'

‘Even a small amount of exercise was really difficult. That’s what people have to deal with when they have pneumonia or other diseases.’

Dr Holloway hopes the lessons from the study will improve care for critically ill adults and children, and even babies in incubators.

‘Now we are looking at heart failure patients to see if low oxygen is the problem and if changing oxygen pathways could improve the lives of heart failure patients. We also need to work out what is behind individual differences in the changes people experience as a result of low oxygen.’

The standard treatment for acute myeloid leukaemia, the most common type of leukaemia in adults, is chemotherapy. But in some people the cancer of the white blood cells can come back after initially successful treatment.

This is thought to be because some cancer stem cells – key cells able to drive the growth of cancers – have remained even after the chemotherapy.

Understanding more about the cancer stem cells present in leukaemia patients could help improve the ability of treatments to get rid of these cancer-driving cells.

Dr Paresh Vyas of the Weatherall Institute for Molecular Medicine at Oxford University and colleagues published a study in Cancer Cell last month that sheds new light on the different populations of stem cells present in leukaemia patients.

The work, funded by the MRC and the Oxford Biomedical Research Centre, could lead to tests that are able to track the presence of cancer stem cells in leukaemia patients, to monitor the progress of treatment or with the aim of preventing later relapse. We caught up with Paresh to learn more...

OxSciBlog: What are cancer stem cells and why are they important?
Paresh Vyas: Stem cells, in general, are primitive cells capable of continually renewing and producing many different types of cell in the body.

Cancer stem cells in particular are primitive cells that are thought to be the source of a cancer. Consequently lots of efforts are being made to characterise cancer stem cells in order to develop therapies that kill these cells and provide better treatments that cure more patients with fewer side effects.

OSB: What did you set out to investigate?
PV: We focused on one cancer called acute myeloid leukaemia. Around 2,200 people in the UK are diagnosed with this cancer every year. Unfortunately up to half of these patients relapse and the disease is very difficult to treat if it returns.

We set out to identify the leukaemic stem cells in acute myeloid leukaemia by studying bone marrow samples (the body’s factory for blood cells) from patients with the condition.

OSB: What did you find about leukaemia stem cells?
PV: We showed that the majority of patients had more than one type of stem-cell-like leukaemia cell in their bone marrow.

OSB: Does this tell us about how leukaemia arises or how the cancer persists?
PV: The confirmation that a single patient can have more than one type of cancerous stem cell driving the disease may explain why treatments for acute myeloid leukaemia are not effective in many cases.

OSB: Can we make use of this knowledge, either in treating patients or in coming up with new therapies?
PV: By identifying new cells that are responsible for driving this leukaemia, we can start to develop new and improved treatments that target these cells.

Most significantly for patients with acute myeloid leukaemia, we can also look at better ways of tracking the disease in individuals and preventing the disease returning.

We've been tracking the progress of the OuTrop Project looking to conserve the environment and wildlife of Borneo's forests.

One of the leaders of the project Susan Cheyne, of Oxford University's WildCRU, is back in the UK to talk about the progress being made and why these forests are vital to the survival of orang-utans, wild cats, and other rare species.

'We've now collected 14,000 hours of animal observations and the gibbon project has over 9,000 hours, making these among the largest studies of their kind,' Susan told us. 'The results are used for conservation purposes but are revealing many interesting discoveries on the behaviour, ecology, social structure and development of two of mankind's closest relatives.'

It's not just about apes, the team have found that Sabangau forest is a strong-hold for birds and mammals such as the elusive Bornean clouded leopard.

'We have data on 3 male clouded leopards and 1 female and we've been investigating threats to these cats including direct and indirect hunting and the possible long-term impacts of habitat loss through fires on the sustainability of the population,' Susan explains.

Along with studying the wildlife, OuTrop also funds a range of conservation activities including replanting areas of the forest and restoring natural water courses by damming artificial drainage canals. It also funds and works with local villagers to help prevent illegal logging and hunting and fight forest fires.

Susan Cheyne talks to BBC Radio Oxford about her work at 3pm on 14 February.

She is a member of WildCRU, part of Oxford's Department of Zoology.