Discovering dementia's molecular structure

The Australian Synchrotron is due to open for general use later this year. The synchrotron will create beams of laser-like intense light that can be used for looking at materials in sub-microscopic detail and for the manufacture of small, precise materials.

It is suitable for both industrial and academic research in almost all areas of science, including:

• drug and vaccine design
• medical imaging
• computer chip development and testing
• food technology and agribusiness
• forensics
• minerals and materials analysis
• environmental science

One of the first proteins to be visualised on the synchrotron is one involved in memory. The protein has the potential to be developed into a treatment for dementia and other forms of memory loss.

The Australian Synchrotron experiment will play a pivotal role in helping scientists from Melbourne's Howard Florey Institute and St Vincent's Institute to analyse how recently identified compounds, which improve memory in rats, interact with the protein, called insulin-regulated aminopeptidase (IRAP).

Data from the experiment, which began on 6 June, will help the scientists refine the structure of these compounds so that they bind better to the IRAP protein, which is the next step in developing a drug that enhances and restores memory.

Dr Siew Yeen Chai from the Howard Florey Institute said these IRAP-binding compounds had already proved to be promising candidates for a drug to treat dementia and other forms of memory loss, including amnesia.

"Within five minutes of giving experimental rats a single injection of these compounds, the animals display a dramatically improved ability to run mazes, which is a standard memory test," Dr Chai said.

Prof Michael Parker, an international leader in structural biology and Australian Research Council Federation Fellow at St Vincent's Institute, was invited to submit projects for the Australian Synchrotron and chose his collaboration project with Dr Chai as one of the first proteins to be analysed at the new facility. For the past few months, Prof Parker's team have been preparing a crystal form of IRAP bound to one of the promising compounds so it can be tested at the Australian Synchrotron.

"The beam will hit the IRAP crystal and will scatter to reveal the 3-D atomic shape of IRAP and show us how the compounds bind to and interact with IRAP," Prof Parker said.

"Once we know how these compounds interact with IRAP, we can refine their structures so they bind more tightly, thus reducing the possibility of side-effects when the compounds are developed into a treatment for humans," he said.

Around six years ago, Dr Chai and her Florey colleague Dr Anthony Albiston discovered IRAP, a specific protein in the brain that certain compounds act on to enhance learning and memory, as well as reverse memory deficits.

For the past four years, the Florey scientists, in collaboration with Prof Parker's lab, have been searching for synthetic compounds that bind specifically to IRAP using a computer model of the protein.

Now the scientists are excited that the Australian Synchrotron experiment will speed up their drug-development research.

"The Australian Synchrotron is helping us to rapidly accelerate this research as we are able to collect, in hours, data on IRAP's structure that would usually take months," Prof Parker said.

"Access to the Australian Synchrotron also allows us to use smaller amounts of the scarce material being tested and provides an accurate protein structure," he said.

This drug development project is being funded by a National Health and Medical Research Council drug development grant, Neurosciences Victoria and the Institute for the Study of Aging in the US, but the Howard Florey Institute is now looking for a commercial partner to invest in this research.