The memory mystery

Dr Siew Yeen Chai has learned over her 20-year research career to be cautious in discussing the potential applications of her work. However, she cannot hide her excitement when she talks about her recent research which may have important implications in understanding the causes and treatment of Alzheimer's disease.

Siew has a personal connection to her research into neurodegenerative diseases as a number of her family and friends have suffered from these debilitating conditions. While she did not choose her research path in response to her family's experiences, she admits the search for the causes, as well as effective treatments, remains close to her heart, especially for the most common of the neurodegenerative diseases, Alzheimer's dementia.

Unfortunately, Siew's family experience is not uncommon. As the population of countries such as Australia grow steadily older, the incidence of neurodegenerative diseases closely linked with ageing will increase.

Siew's research focuses on an enzyme identified in the brain by her lab, insulin-regulated aminopeptidase (IRAP). Siew and her colleagues found that blocking the activity of this enzyme in the brain results in improved performance in memory tasks.

While working at the Howard Florey Institute prior to joining Monash University, Siew's team, together with collaborator Professor Michael Parker of St Vincent's Institute, began using a computer-based drug screening strategy to identify compounds that would act as an IRAP inhibitor. Using these in silico methods they were able to effectively and accurately sort through 1.5 million compounds to find ones with predicted high affinity for IRAP, which they were then able to develop into drug-like IRAP inhibitors. When introduced to normal rodents, these IRAP inhibitors improved performance in memory tasks. What was not expected was that when these newly discovered IRAP inhibitors were administered into Alzheimer's mouse models, they not only reversed memory loss, but actually showed signs of stopping the deposits of amyloid plaques, the pathological hallmarks of Alzheimer's disease, in the brain.

IRAP plays a role in muscle and fat cells, enabling glucose to be taken up in response to insulin. Quite what its role is in the brain, and the specific link between blocking its activity there and improved memory performance as well as the development of Alzheimer's disease, is still unclear. This is the focus of Siew's current research endeavours.

For Siew, with her acute awareness of the debilitating effects of Alzheimer's, the recent findings from her lab have provided the highlight of her research career to date.

"When we first stumbled on this discovery I thought, yes, this is meant to be," she says.

What has really interested the scientific community as well as the pharmaceutical and biotech industries are the indications that blocking IRAP activity might not only reverse memory loss, but also stop the progression of Alzheimer's disease. Siew has received a grant from Commercialisation Australia to work in partnership with Biolink to attract a pharmaceutical partner for her research.

"Now we are working on development of a second class of compounds that demonstrate the same effect as well as discovering the mechanism of the drug's action so that we have confidence that blocking IRAP activity has the desired effect of stopping the progression of Alzheimer's disease," Siew says.

Siew's work has led to the publication of 128 research papers and book chapters, and she has been awarded seven patents.