Your brain in a flash Dementia’s research – a year of discovery

Melbourne Dementia Research Centre

Federal Health Minister, Greg Hunt, launched the Melbourne Dementia Research Centre in October, establishing a collaborative team of researchers from the Florey and the University of Melbourne.

Headed by one of the world’s most cited neuroscientists, Professor Ashley Bush, the dementia centre has already had a major impact on Alzheimer’s research. The group has announced a trial to assess the impact of iron in the brain on the progression of Alzheimer’s disease. Ashley says: “The dementia centre will focus on integrating basic and translational research into dementia, with a special focus on clinical trials and clinical longitudinal studies.”

The importance of finding a cure for dementia is growing every day with more than 400,000 Australians currently living with the disease, and another 100,000 more expected to be diagnosed within less than a decade.

Over 200 researchers are involved, all of them dedicated to finding improved diagnostics, treatments, and ultimately a cure for dementia. To date it has received funding of over $22 million from the National Health and Medical Research Council, and $4 million in support from funders and major donors.

Passing the sniff test

Dr Simon James combines his polymath knowledge of chemistry, physics and biology to find causes of dementia. The secret to his success? A transparent, one-millimetre-long roundworm who would rather be in the soil than a Synchrotron.

Ageing is the biggest risk factor for a host of diseases, including dementia. Why?

SJ One of the greatest mysteries is why the risk rises so dramatically as we age. Most people living with Alzheimer’s disease are 65 or older and for those over age 85, the risk rises to nearly 50 per cent.

Surely ‘ageing’ is a pretty complex phenomenon. How do you study the biology of ‘ageing’?

SJ The brain is a monstrously complex bit of biology; made up of roughly 170 billion cells or roughly half the number of stars in the Milky Way. Throw in myriad changes and individual experiences that accumulate over a lifetime and it becomes very difficult to identify the specifics driving age-related disease. Luckily, we are able to simplify some aspects of the brain’s biology using a tiny worm known as the Caenorhabditis elegans. Its genome is fully mapped, it’s the first animal to have a complete neuronal wiring diagram and, usefully, it is very easy to look after and has a short lifespan of about two weeks.

How

useful can studying a worm really be?

SJ Although the whole animal only has 1000 cells or so (humans have a few trillion) and 302 of these are neurones, we share an enormous amount of biochemistry, making it an ideal model organism. Neurones (the brain cells that die off in Alzheimer’s) are very active and generally are not replaced. This is as true for our worms as it is for people. Compare a 2-stroke Victor lawnmower with James Bond’s Aston Martin Vanquish S (my much-coveted car). The two machines are very different but both use internal combustion engines. So, while our human, Vanquish-like nervous systems do all sorts of important things that the worm’s humble, mower-like nervous system does not, many of the central, essential processes happen in both.

So which process are you actually studying?

SJ I focus on how neurones manage the trace mineral iron. To build on the analogy above, in cell metabolism iron plays a role akin to a spark plug. If a spark plug is firing too much or too little, neither of those machines will run smoothly, and eventually the misfiring will damage the engine’s internals. Every cell in our body depends on iron to “fire” correctly but as neurones are so incredibly active they are more sensitive to “misfiring” than most other cell types. The long life of a neurone means there is greater opportunity for small misfirings to accumulate and cause trouble. We study how the worm’s neurones handle iron and use these insights to increase our understanding for what’s going on in the human context.

Boosting Dementia Fellowships

What have the worms taught you about human ageing dementia?

SJ Just like humans, worms show changes in iron metabolism as they age. The cells can no longer handle iron properly –something like spark plugs wearing out with time and never being replaced. We have actually been able to see this happening in worms using the Australian Synchrotron. It may seem strange that we need a 400 metre-long, high powered X-ray microscope to study such a small creature, but it allows us to study iron biochemistry in a way simply not possible in humans.

What’s next?

SJ One of the best things about working at the Florey is the breadth of expertise. While we are chasing nitty-gritty iron biochemistry, other scientists are chasing down how our findings apply in a clinical context and all of this work together informing a search for a cure. We lead the world in identifying iron’s role in dementia. The team incorporates basic biology with the latest clinical information to carve out an understanding of the causes of this devastating disease.

The Federal Government has declared dementia a priority research focus and funded the NHMRC Boosting Dementia Research Fellowships. Congratulations to the four Florey Fellows in 2017 – Dr Thibault Renoir, Associate Professor Brad Turner, Dr Daniel Scott and Associate Professor Blaine Roberts. They have been awarded a combined $2.88 million over three years to continue their innovative research into gene-environment interactions, develop blood-based biomarkers to diagnose Alzheimer’s, produce next-generation receptor targeting therapeutics and improve high-throughput drug screens for frontotemporal dementia.

Victoria Fellowship

Dr Erin McAllum has been awarded a prestigious Victoria Fellowship to travel to the University of Bordeaux, France, to learn more about a specialised chemical imaging technique. The expertise she gains will then be brought back to Australia to further her research into dementia with Lewy bodies. You can watch Erin explain her work in more detail on our YouTube channel.

Dr. Mathias Dutschmann wants to discover how we generate complex breathing patterns in the brainstem. His group has developed sophisticated ways to reproduce these patterns in the lab, like sniffing in response to airborne irritants. Significantly, the group has observed cell death in the brainstem occurring much earlier than in the higher brain regions responsible for memory loss and personality changes in Alzheimer’s. People in the early stages of dementias and motor neurone disease often have subtle problems with complex breathing patterns. Matthias believes these could be detected using a simple “sniff test” given by a GP. If a patient fails the “sniff test”, they could be recommended for further Alzheimer’s tests, speeding up diagnosis and aiding trial recruitment.