Science Spin January 2007

UCD pushes frontiers of brain research

By Sean Duke

The brain, it's the essence of what we are, our memories, all our learning, our personality, our emotions - love, hate, ambition. Without our brain we are nothing, but for centuries, mankind knew little of its workings. Diseases of the brain were, and are, greatly feared. It was as if these diseases - depression, schizophrenia and dementia - just struck down the sufferers down like a bolt from the blue, without warning or explanation. Now, however, finally, in the 21st century, researchers are starting to understand what makes a brain tick, how we learn, how we remember, why we behave as we do, and how brain diseases arise.

UCD is right at the forefront of this brain research, both in Ireland and abroad. It is home to a large 'cluster' of researchers who can be termed 'neuroscientists' in that they share a common research interest in the brain and its workings. These scientists are a powerful and weighty bunch, and - crucially - they can approach the same problem from many different angles, given that they have a wide variety of training and scientific backgrounds, whether that is Physiology, Microbiology, Medicine or Zoology.

The proximity of life scientists at UCD to each other has been an important catalyst for generating cross disciplinary neuroscience research. Whether it is study of the prion as a model for neurodegenerative disease, developing ways to 'image' diseased brains, or pinpointing the mechanisms that underlie Alzheimer's and Parkinson's disease it's all happening somewhere on the UCD campus.

Prions

The prion protein, as most people would know, is the protein that is responsible for BSE, or 'mad cow disease' in cattle, and its cousin - CJD in humans. The devastating condition CJD is extremely rare, so this would perhaps suggest that study of the prion protein and how it works is really an academic exercise, important simply for animal health.

This in fact, is far from the case, as the study of how abnormal prion protein causes disease can provide a model for understanding Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. There are common mechanisms between prion diseases and other brain diseases and these can best be studied in animal models.

One of the key prion research people at UCD is Professor Mike Scott, who before coming to Ireland was working at the famous laboratory of Nobel Prize winner Stanley Pruisner at the University of California, San Franscisco. Pruisner won the Nobel prize for Medicine in 1997 for his discovery of the Prion protein, and its links to BSE and CJD.

Professor Scott is just now at the beginning of a four year project to set up his own prion laboratory at UCD, and he wants this laboratory to be a collaborative effort with other researchers who are interested in the wider field of neurodegenerative diseases.

One aim, said Prof Scott, would be to find out if there are other agents in existence, like the prion protein, that cause neurodegenerative diseases, and if so, which genes control these agents, and what are the mechanisms by which they operate?

The overarching goal is, he said, to develop model animal systems for studying all neurodegenerative diseases, while identifying the genes that are important in instigating prion disease and determine if they are important.

One researcher who would be very keen to get access to animal models for studying prion disease is industrial microbiologist Dr Hilary McMahon.

In an recent important development, Dr McMahon identified an anti-prion agent. This agent, she said, cleared all cells of the abnormal prion protein in culture. She would like to take this further and test the agent in animal models, and look for more anti-Prion agents. Such agents could be used to treat neurodegenerative disease beyond CJD.

The Prion protein, said Dr McMahon, is present in all cells of our body, though its function remains a mystery. Scientists don't know why it exists or what its role is in the cell - given its widespread existence researchers believe it must have some positive role.

One theory is that normal prion is turned into abnormal prion in response to stress, but, the question then is, why a cell would create the potential for its own destruction, as a response to stress.? The honest answer is, Dr McMahon says, we don't know, but she would certainly like to get answers through more collaborative research.

Depression

In days gone by, depression, schizophrenia and other mental illnesses were poorly understood, but that is changing and researchers are now starting to see that mental illness, like Alzheimer's or Parkinson's, are due to observable changes in the brain.

Professor of Psychiatry, Kevin Malone, is working with Professor Richard Reilly, School of Electrical, Electronic and Mechanical Engineering, in a fascinating and unique cross school research collaboration into 'imaging' the diseased brain.

This study, called the functional neuro-imaging study, is examining the brains of people with suicidal depression, and is funded by the American Foundation for Suicide Prevention. St Vincent's Hospital, Elm Park where Professor Malone is based, is running this study in conjunction with sister hospital St Vincent's Fairview, and all of the depressed and suicidal people taking part are volunteers.

The study makes use of a cap worn on the head that is equipped with 128 sensors positioned in key locations of the head. An image is generated using various imaging technologies, software is then applied, and the image is finally interpreted.

The cap and the software have been developed by Professor Reilly's research team, while the analysis of the images is conduced by Dr Rob Whelan and other members of Professor Malone's team. It is a perfect match of engineering and scientific talents.

The lab at St Vincent's is an EEG (electroencephalography )lab. This is the technique where the electromagnetic fields of brain cells, or neurons, can be detected, to indicate which areas of the brain are active or inactive. Eventually it is hoped that such imaging studies will provide an aid to clinicians in diagnosing suicide and mental illness.

This imaging work builds on earlier work by Prof Malone when he developed a method for visualizing serotonin (a key neurotransmitter in the brain) function in the brain of living patients using PET, or Positron Emission Tomography.

Alzheimer's disease

This is the most common of all neurodegenerative diseases and affects in the region of 15 million people around the world, and 60,000 people in Ireland. The disease, which affects 10 per cent of people over 65 and 50 per cent of people over 85, is characterised by shrinkage of the brain regions involved in learning and memory.

Professor Dominic Walsh is a top class UCD Alzheimer's disease researcher who has been lured back to Ireland, from the USA, where he was working at the Harvard Institutes of Medicine. Professor Walsh is very interested in the amyloid beta protein, which plays a critical role in initiating Alzheimer's disease.

In the past decade or so, Prof Walsh has unravelled much of the biochemical pathway that leads to the development of Alzheimer's disease and this knowledge is crucial in the drive to develop methods to disrupt the disease along its pathway.

The Alzheimer's pathway begins with the action of two enzymes, beta and gamma secretase. These cleave the amyloid precursor protein. This leads to the production of the amyloid beta protein itself. The next stage, and this is the critical stage, is when the beta proteins become oligomers, and in this form, they become fibrils that are deposited in the brain, causing severe damage.

The amyloid fibrils are found in structures called 'plaques' and these structures litter the brains of those with Alzheimer's disease. The problem is that once these structures are seen the disease has already caused a lot of damage.

Professor Walsh is keen to work with prion researchers Mike Scott and Hilary McMahon he recognises that there are similarities between the prion disease pathway and Alzheimer's disease.

Prof Walsh says that given the overwhelming data to support the view that amyloid beta protein plays a central role in Alzheimer's disease, understanding how this protein alters brain function is vital for the development of therapies for the disease.

Prof Walsh states that finding a way to lower the amyloid beta protein to levels that prevent oligomerization may be one therapeutic strategy for the treatment of Alzheimer's disease. But, more work has to be done to nail possible treatments down.

Dr Caroline Herron is working closely with Prof Walsh on cracking the Alzheimer's story. She is interested in how amyloid beta protein appears to destroy hippocampal synaptic plasticity. The hippocampus is the area of the brain associated with memory and learning, and plasticity, when used by neuroscientists means the ability of the brain to alter its structure in order to lay down new memories and learning.

It appears that the plasticity of the brain takes place at the level of the synapses - the tiny gaps across which individual nerve cells communicate. Clearly, greater knowledge of the role of the destructive beta protein at this level could lead to new drugs for Alzheimer's or other neurodegenerative diseases.

Parkinson's disease

This is another common neuro-degenerative disease, with an estimated 6,000 people in Ireland suffering from its symptoms. Professor Timothy Lynch, Consultant Neurologist, Mater Hospital, UCD, has set up an All Ireland Parkinson's Disease Research Group, along with medical colleagues and fellow Consultant Neurologists Tim Counihan, University College Hospital Galway and Mark Curran, Belfast.

Professor Lynch, formerly of the Mayo Clinic, USA, has established a 'research cohort' comprising of 600 to 700 people with Parkinson's Disease, in conjunction with the Mayo clinic and is in the process of setting up collaborations with colleagues at the Conway Institute, including Prof Walsh, who are also interested in neurodegenerative diseases.

Despite many years of research, not enough is known about the causes of Parkinson's disease, but Prof Lynch believes that Ireland, with its small, and common gene pool, is an ideal place to try and pin down neurodegenerative risk factors.

"I'd like to have more (research) links with the Conway Institute and to translate the findings from that research into my clinical practice. I would also like to get clinical trials going for Parkinson's disease, to see what agents and what genotypes are involved. All of this information will be spat out of basic neuroscience," said Prof Lynch.