Dr. Laura Aitken, a senior postdoctoral research fellow with Professor Frank Gunn-Moore’s group, is currently leading a Rosetrees-funded project that aims to identify novel drugs for Alzheimer’s disease, at the University of St Andrews. In this project Laura has been investigating the role of amyloid binding alcohol dehydrogenase, more commonly known as 17β-HSD10. She has validated its potential to act as a drug target. The hallmark, toxic protein in Alzheimer’s disease, amyloid, is a binding partner of 17β-HSD10. So, by inhibiting its activity, this could slow down or prevent the development of Alzheimer’s.
Earlier Rosetrees funding supported Professor Gunn-Moore’s team in discovering the consequences of this novel interaction, between 17β-HSD10 and amyloid. In the brain, the normal role of 17β-HSD10 is to help make energy. This process becomes dysfunctional in Alzheimer’s disease, which leads to the death of nerve cells. This takes place when glucose levels have decreased. Furthermore, they determined direct substrates of 17β-HSD10 allowing them to measure 17β-HSD10 activity in living cells. They also found specific fat (or lipid) changes in the brain that have been linked to pathogenesis of Alzheimer’s disease.
Following on from this work, Rosetrees begun funding Laura to expand the teams research into the more drug discovery aspect of Alzheimer’s disease. Here she successfully evaluated a series of potent compounds for 17β-HSD10 with a collaboration they had forged with partners in the Czech Republic. Laura also established several assays to test for cellular toxicity, and to assess the ability of the compounds to directly inhibit 17β-HSD10 in cells. This produced a pipeline of tests allowing them to subsequently rank their compounds in order of effectiveness, and lack of toxicity.
This is what Laura had to say:
“Currently, there are no disease modifying therapies for Alzheimer’s disease and the constant need to learn, improve and challenge our knowledge of the disease to achieve this has been a huge driving factor behind my research.”
In their current Rosetrees-funded research, Laura is now implementing this and testing their hit compounds in cells that are better models for Alzheimer’s disease. Using this approach, they can avoid the use of animal models. In their latest progress, they have established neuronal cell models, and began metabolomic studies to determine what energy production changes there are in these Alzheimer’s disease like cells and if this can be rescued on treatment with their compounds. They have also recently published in Molecules, showing their evaluation of a novel, different series of compounds, finding increased potency for these compounds compared to previously published data. This work with further characterisation in other Alzheimer’s disease models could become potential drugs.
Laura also said:
“We really hope that our research, kindly funded by Rosetrees Trust, will lead to a major advancement in both our further understanding of Alzheimer’s disease and one day lead to a treatment for the disease.”
Written by: Dr. Rebecca Downing and Dr. Laura Aitken