LC-DIA-MS/MS reveals aging- and pathology-specific molecular alterations in aging and Alzheimer’s disease
Researchers from Boston University Chobanian & Avedisian School of Medicine (MA, USA) have developed a novel mass spectrometry-based workflow using LC-DIA-MS/MS to uncover molecular changes in aging and neurodegeneration, offering new insights into Alzheimer’s and Lewy body disease.
Aging is the strongest risk factor for neurodegenerative disorders such as Alzheimer’s disease (AD) and Lewy body disease (LBD), driving molecular changes that predispose the brain to synaptic dysfunction and proteinopathy. Current diagnosis relies on documenting mental decline and symptoms are often overlooked as normal signs of aging, meaning AD and LBD are frequently identified after irreversible pathology has developed.
Glycosylation and extracellular matrix remodeling are crucial processes for protein folding, stability and cell signaling and represent underexplored mechanisms linking aging to neurodegeneration, opening avenues for biomarker discovery. Mass spectrometry-based glycoproteomics and glycomics studies, however, have remained limited until now.
In this new study, the researchers used a unique, on-slide tissue digestion workflow using liquid chromatography data-independent acquisition–tandem mass spectrometry (LC-DIA-MS/MS). They first studied brain tissue from young and aged experimental models to understand how normal aging affects the brain and later studied human brain tissue from people with AD with or without LBD.
For each sample, they took brain sections mounted on glass slides and treated a 5 mm marked circle with enzymes that release sugars and proteins directly from the tissue. They then used LC-DIA-MS/MS to measure and compare thousands of proteins and brain sugars across the model and human brain tissues, age groups, brain regions and disease conditions. This method demonstrated that protein and sugar level changes occur with aging and AD brains, particularly when AD co-occurred with LBD.
“Our study elucidates how the brain changes with aging and with diseases such as AD in the presence or absence of LBD pathology at a highly detailed molecular level. Understanding these changes is important because they begin years before symptoms such as memory loss or movement problems appear, explained Manveen Sethi, corresponding author and Associate Professor at Boston University Chobanian & Avedisian School of Medicine. “Clinically, this work may help scientists discover new biomarkers to support earlier diagnosis, improved disease classification or better treatment monitoring.”
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This method could be applied to many other diseases and clinical tissue samples:
“Our hope is that this research will provide scientists with a robust and high-resolution spatial mass spectrometry glycomic and proteomic workflow from minimal tissue, providing a framework for understanding aging and neurodegeneration and biomarker discovery to support better diagnosis and treatments, and improved quality of life for people,” added Sethi.
The study established a robust DIA-based, on-slide digestion platform for high-resolution spatial glycomics and proteomics from minimal tissue, revealing aging- and pathology-specific molecular alterations relevant to neurodegeneration and providing a framework for biomarker discovery.
