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| CSIRO | SOLVE | Issue 4 Aug 05 | |
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ARTICLE
PREVENTATIVE HEALTH: The Battle to Save the Baby Boomers' Brains
GRAEME O'NEILL REPORTS ON SOME OF THE LATEST RESEARCH INTO ATTEMPTS TO THWART A LOOMING CRISIS IN HEALTH CARE AS OUR MEDICALLY ENHANCED BODIES START TO INCREASINGLY OUTLAST OUR MINDS. The number of Australians diagnosed with dementia is predicted to exceed 200,000 this year, or one per cent of the population, a milestone presaging the epidemic to come. CSIRO’s Preventative Health Flagship is moving to evolve an existing partnership with Neurosciences Australia, a consortium of leading Australian neuroscientists, into a major project to investigate the pathological processes involved in the most common form of dementia, Alzheimer’s disease (AD). The project aims to identify and characterise molecular targets for new drugs or preventative strategies that will prevent or delay the onset of the devastating neurodegenerative disorder. Time is short. The oldest members of the great post-World War 2 population pulse of Baby Boomers are entering AD territory. The disease process begins decades before individuals exhibit obvious symptoms of memory loss and cognitive decline.
In March this year, an Access Economics report, ‘Dementia Estimates and Projections: Australian States and Territories’, projected that the number of new dementia cases will rise exponentially in the coming decades. By 2050, it will reach 175,000 per year – a four-fold increase, and more than the total number of cases in Australia in 2000. The report, prepared for Alzheimer’s Australia, predicted that the total number of dementia patients in 2050 will exceed 730,000, or 2.8 per cent of the population. However, it noted that any therapeutic advance that merely delayed the age of onset of AD would have a dramatic impact on the future number of cases, and the real costs of dementia. CSIRO brings its long-established expertise in structural biology and molecular modelling to the project, while Neurosciences Australia is contributing scientific and clinical insights into the disease process and animal models of AD. Neurodegenerative diseases expert Professor Colin Masters, of Melbourne University’s Department of Pathology and lead researcher in the project, says a misfolded protein called beta-amyloid is “at the very centre of the causation of AD”. The collaboration revolves around this neurotoxic protein. Beta-amyloid aggregates in the ageing brain, clogging it with toxic amyloid plaques and fibrils that eventually result in massive loss of neurons involved in memory and cognition. Enzymes cleave beta-amyloid from a larger protein, amyloid precursor protein (APP). In 1987 Professor Masters and a colleague, Professor Konrad Beyreuther of the University of Cologne, took a major step towards understanding AD by cloning the APP gene. The APP’s function remains unclear, but it has two metal-binding domains, indicating some role in normal copper metabolism. When the protein is broken down and recycled in the Alzheimer brain, the amyloid fragment, which embodies one of the two copper-binding domains, escapes degradation. It misfolds and aggregates, forming neurotoxic amyloid plaque. In the 1990s, one of Professor Masters’ former PhD students, Dr Ashley Bush, proposed a new explanation of how beta-amyloid intoxicates and kills neurons. Now well accepted, Dr Bush’s theory proposes that the metal-binding domain captures highly charged copper and zinc atoms (ions) that then cause the fragments to bind to each other. They form highly insoluble deposits and then spawn hydrogen peroxide molecules that decompose rapidly into water and are highly reactive hydroxyl (OH.) radicals that attack neuronal lipids and proteins. Ailing neurons eventually succumb en masse to the toxic insult. Dr Bush has shown that metal-chelating compounds that sequester copper and zinc literally pull the pins from the highly insoluble amyloid plaques in-vitro, causing them to fall apart. Dr Bush and his colleagues formed an ASX-listed company, Prana Biotechnology, to exploit the discovery and develop new metal-chelating molecules to treat and prevent AD. The design of more efficient, low-toxicity metal-chelating drugs depends on defining the 3D molecular structure of the amyloid metal-binding domain, so ‘plug drugs’ can be designed to prevent it binding copper and zinc ions. Professor Masters is “very optimistic” that drugs targeting the core of the disease process can halt the disease – or better still, prevent it. He describes amyloid as being “at the centre of causation of AD” but for more than a decade, the protein’s insolubility has frustrated efforts to crystallise it, a prerequisite to determining its structure. Protein structures are determined by probing crystals with focussed X-ray beams from a synchrotron. Australia’s first synchrotron is under construction near Monash University in Clayton, but until it comes on-line in 2007, CSIRO crystallographers are hiring beam lines at synchrotrons in the US and Japan. Dr Jose Varghese, of CSIRO Health Sciences and Nutrition in Parkville, Melbourne, heads a structural biology research group that is attempting to determine the structure of beta-amyloid and use powerful computer-based simulations of its molecular structure to investigate its misfolding and aggregation behaviour. A member of Dr Varghese’s team, Dr Ian Macreadie, has constructed a composite gene that, when introduced into yeast cells, expresses a fusion protein combining beta-amyloid with maltose-binding protein. The conjoined proteins form a soluble complex that, when purified could finally yield crystals suitable for structural analysis. Dr Varghese says his team’s in-silico modelling will be matched with experimental observations to determine how point mutations (single-base DNA changes) influence individual susceptibility to AD. Some mutations result in severe, early-onset, inherited forms of the disease. Dr Varghese says his team will determine the structure of beta-amyloid molecules that Dr Roberto Cappai and Dr Keven Barnham, in Professor Masters’ team, have complexed with copper and zinc ions to simulate their natural occurrence in amyloid plaque. “We’ll use various synchrotron techniques to measure X-ray absorption, which will tell us how the protein binds to copper, zinc and perhaps iron,” he says. “If we can understand how beta-amyloid forms and aggregates, and then develop a detailed structural understanding of how amyloid binds to metal, we will have a better chance of designing drug molecules to prevent the reaction taking place. “People now suspect that almost any protein has the potential to form amyloid under the right conditions. But most proteins require really extreme conditions to do so. However, amyloid that forms under normal physiological conditions is invariably associated with disease. In the brain, they result in neurodegenerative diseases like Alzheimer’s disease and Creutzfeldt–Jakob disease.” The collaborative research project is being coordinated by Associate Professor William Hart, chief executive of Neurosciences Australia. “The science being brought to this project combines biology – how the protein works in nature, and its role in the biology of Alzheimer’s disease – and physical chemistry, the 3D structure and chemical behaviour of the molecule,” Professor Hart says. “The participants have in-depth skills in their particular fields that are very complementary.” Dr Trevor Lockett, Novel Diagnostics Research Stream Leader with CSIRO’s Preventative Health Flagship, says the project is also developing assay systems to screen for food-based and other small-molecule compounds that might prevent or delay AD by disrupting the amyloid–metal ion binding reaction. “The assays will mimic the processes involved in the abnormal folding of amyloid and its production of free radicals, and test the ability of synthetic and food-derived small molecules to inhibit such processes,” Dr Lockett says. INVESTIGATION To identify and characterise molecular targets for new drugs that will prevent or delay the onset of Alzheimer’s disease (AD). TARGET A misfolded protein, beta-amyloid, is at the centre of the causation of AD whose structure needs to be determined. For further information contact: |
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