(Boston)—Neurodegenerative disorders such as Alzheimer's disease (AD) are typically diagnosed after irreversible pathology has developed. Aging, the strongest risk factor, drives molecular changes that predispose the brain to synaptic dysfunction and proteinopathy (neurodegenerative diseases characterized by the abnormal folding, aggregation, and accumulation of specific proteins within neurons or brain tissues). Glycosylation and extracellular matrix (ECM) remodeling are processes crucial for protein folding, stability and cell signaling and represent underexplored mechanisms linking aging to neurodegeneration, opening avenues for biomarker discovery; yet mass spectrometry-based glycoproteomics and glycomics studies have remained limited until now.
Using a unique on-slide tissue digestion method and advanced mass spectrometry technique that captures substantially more molecular information than prior methods, researchers from Boston University Chobanian & Avedisian School of Medicine have discovered protein and sugar level changes that occur with aging and Alzheimer’s disease brains, especially when Alzheimer’s disease co-occurs with Lewy body pathology.
“Our study elucidates how the brain changes with aging and with diseases such as Alzheimer’s disease in the presence or absence of Lewy body 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. Clinically, this work may help scientists discover new biomarkers to support earlier diagnosis, improved disease classification or better treatment monitoring,” explains corresponding author Manveen Sethi, PhD, assistant professor of biochemistry and cell biology at the school.
The researchers studied brain tissue from young and aged experimental models to understand how normal aging affects the brain. Second, they studied human brain tissue from people with Alzheimer’s disease with or without Lewy body pathology. For each sample, they took brain sections mounted on glass slides and treated a small, marked area (5mm circle) with enzymes. These enzymes release sugars and proteins directly from the tissue. They then used a highly sensitive mass spectrometry technique to measure and compare thousands of proteins and brain sugars across the model and human brain tissues, age groups, brain regions and disease conditions.
According to the researchers, the method developed in this study could be applied to many other diseases and clinical tissue samples, spatially to an area of interest on the tissue section, opening new possibilities for research. “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,” adds Sethi.
These findings appear online in the Analytical and Bioanalytical Chemistry journal.
Funding for this study was provided by the National Institute of Health (NIH) grant R01AG075876, BrightFocus Foundation Research Fellowship Award A2020687F, and Boston University Clinical Translational Science Institute Pilot Grant Award 1UL1TR001430.
Analytical and Bioanalytical Chemistry
Experimental study
Cells
Mass spectrometry analysis of young and aged mice and human Alzheimer’s disease with Lewy body pathology using on-slide tissue digestion
28-Feb-2026