The missing piece of the Alzheimer’s puzzle

Mass spectrometry innovation tracking lipid changes in the aging brain

According to Alzheimer’s Disease International, over 55 million people worldwide are living with Alzheimer’s disease and related dementias – a shocking statistic set to almost double every 20 years.

To date, much research has focused on the role of proteins in the pathology of the disease. But a trailblazing international study to uncover the crucial part that lipids play in declining health and function as we age could hold the elusive key to improving diagnosis, treatment, and prevention. 

The US$2.8 million project, funded by the National Institutes of Health, is a collaboration between the University of Maryland, Baltimore (UMB), Belgian bioinformatics company Aspect Analytics, and Associate Professor Shane Ellis of UOW Molecular Horizons. 

“There’s very little known about how lipids change in ageing, but we do know that they are intricately involved in a lot of metabolic functions and diseases,” Dr Ellis explains. 
“Our research focuses on developing techniques to locate these lipid molecules, or fat molecules, in tissue sections and understand how they have been metabolised and modified through disease.” 
Dr Ellis and his team will use the mass spectrometry technologies he has developed in Molecular Horizons to look specifically at lipid metabolism and changes in the brains of mice and gain a molecular understanding of what leads to Alzheimer’s or its symptoms. 

Unique capabilities

The five-year project is led by UMB’s Dr Alison Scott, who specialises in the imaging and study of lipids in infectious and other diseases. She is joined by her University of Maryland colleagues Dr Dave Rasco and Behtash Babadi, offering respective expertise in spatial transcriptomics and artificial intelligence.  
Dr Scott sought out Dr Ellis as a co-principal investigator for his innovative lipid analytical techniques and Molecular Horizon’s world-leading mass spectrometry facilities. UOW has been awarded US$612,000 of the total funding. 
“Historically, lipid droplets have remained poorly understood, though they are described in the initial characterisation of the disease by Alois Alzheimer,” Dr Scott explains. 
“By combining the powerful new lipid analytical techniques pioneered by Dr Ellis we can now map lipids and lipid droplets with high molecular and spatial detail to address this gap and advance our understanding of this devastating disease.” 
Dr Ellis says UOW is arguably the best institution in Australia for mass spectrometry imaging research. 
“Our technologies are unique not just in Australia but globally, including a high-resolution laser post-ionisation system that improves sensitivity 100-fold,” he says. 
“Mass spectrometry is ideal for this research because it can detect hundreds of different molecules in the same experiment. It’s the only technique that delivers such multiplexed imaging and enables chemically-specific imaging of small molecules such as lipids, which enables us to understand molecular changes even down to the level of a single cell.” 
Dr Ellis holds a UOW PhD in mass spectrometry and spent eight years in the Netherlands developing new imaging technologies and instrumentation before securing an ARC Fellowship. He returned to UOW in 2020 to establish the world-leading Molecular Horizons Mass Spectrometry Imaging Lab and has played a decisive role in growing UOW’s international reputation for excellence in the field.  
The third co-principal investigator in the project is molecular image data analysis and bioinformatics expert Dr Heath Patterson, Director of Spatial Biology Bioinformatics at Aspect Analytics. He will integrate the diverse experimental data collected through microscopy, spatial transcriptomics, and high-resolution mass spectrometry imaging to enable a more holistic understanding of molecular changes. 
“Our fruitful relationship with Dr Ellis’ lab on several projects has helped us develop our platform and resulted in multiple publications,” says Dr Patterson.  
“This grant is a fantastic opportunity to develop our bioinformatics toolbox for spatial omics data analysis combining state-of-the-art mass spectrometry imaging, spatial transcriptomics, and spatial proteomics within a formidable biological study. We’re aiming to transform deep biological knowledge of lipids into useful software for spatial omics data analysis.” 
Dr Ellis is excited by what this multidisciplinary collaboration will enable. 
“Through this collaboration, we will be able to access extremely high-quality samples alongside expertise in the complex computation required to facilitate greater discovery through our advanced imaging technologies,” he says. 
“It’s great to see the techniques we have developed here becoming useful across so many different applications and in such high demand among leading international research institutions.”  

Scalable impact

he research has vast potential to transform the lives of the millions of people affected by Alzheimer’s disease around the world and those who care for them. 
“Currently available treatments are limited and are primarily focused on managing symptoms,” says Associate Professor Ellis. 
“But if you can understand the early metabolic signs that you might develop Alzheimer's, then you can catch it early and start treating it early. We can’t do this without having a better understanding at the molecular level of exactly what is changing, where these changes are happening, and how they are implicated.  
“This can then translate into the development of novel drugs and therapies to treat lipid dysregulation and reduce – even prevent – complications of ageing.” 
And the impact is not confined solely to Alzheimer’s and related dementias. Dysregulated lipid homeostasis is linked to inflammation, diabetes, Parkinson’s disease, Gaucher disease, forms of liver failure, and countless other pathologies yet to be investigated. Associate Professor Ellis is concurrently applying his expertise in mass spectrometry and lipids across a range of transformative research projects. 
“We're working on some major research projects on Parkinson’s disease with funding from the Michael J Fox Foundation, including projects looking at lipid metabolism in stem-cell-derived neurons from Parkinson’s patients together with UOW’s Professor Lezanne Ooi, as well as human post-mortem brain tissue, also with Aspect Analytics. We are also applying our technologies to understanding lipid metabolism within heterogeneous cancers including pancreatic cancer, prostate cancer, and breast cancer,” Associate Professor Ellis says. 
The innovative technologies used in this research are also being applied to test new drugs in development, tracking where they end up and how they metabolise. 
“It’s a really broad technology platform that we can apply to many different biological questions and we’re continuously developing and enhancing it to offer better spatial resolution and sensitivity.”