Mass Spectrometry Technique Detects Protein and Sugar Changes in Neurodegeneration

Aging, the strongest risk factor, can drive molecular changes that predispose the brain to synaptic dysfunction and protein aggregation. Glycosylation and extracellular matrix (ECM) remodeling have been highlighted as underexplored mechanisms that may connect aging to neurodegeneration and support biomarker discovery, yet comprehensive analyses have been limited. Researchers now report new findings enabled by a spatially targeted, high-information mass spectrometry workflow.

Researchers at Boston University Chobanian & Avedisian School of Medicine utilized a unique on-slide tissue digestion approach paired with an advanced mass spectrometry technique that captures substantially more molecular information than prior methods. The workflow releases proteins and sugars directly from a precisely marked, 5 mm circular region of tissue sections using enzymes. This enables high-sensitivity, spatially resolved profiling of both glycoproteomics and glycomics from minimal material.

The team first analyzed brain tissue from young and aged experimental models to define molecular features of normal aging. They then examined human brain sections from individuals with Alzheimer’s disease, with or without co-occurring Lewy body pathology. Thousands of proteins and brain sugars were measured and compared across model and human tissues, age groups, brain regions, and disease conditions.

The investigators identified protein and sugar level changes associated with aging and Alzheimer’s disease, with particularly notable alterations when Alzheimer’s disease co-occurred with Lewy body pathology. According to the researchers, the method can be applied to many other diseases and clinical tissue samples, allowing spatial analysis of regions of interest on a slide. The findings appear online in Analytical and Bioanalytical Chemistry.

“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,” said Manveen Sethi, PhD, assistant professor of biochemistry and cell biology at Boston University Chobanian & Avedisian School of Medicine.

“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.

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Boston University Chobanian & Avedisian School of Medicine