Unveiling exosomal biomarkers in neurodegenerative diseases: LC-MS-based profiling

Exosomes, small extracellular vesicles secreted by various cell types, play a critical role in intercellular communication and are increasingly recognized as key players in the progression of neurodegenerative diseases (NDs). Their ability to carry and propagate pathogenic proteins such as amyloid-beta, tau, and alpha-synuclein have established exosomal biomarkers as both key players in disease pathology and promising indicators for early diagnosis. Liquid chromatography-mass spectrometry (LC-MS) has emerged as a powerful tool for the comprehensive analysis of exosomal cargo, enabling the identification of proteins, metabolites, and other molecules associated with neurodegeneration. This review explores the structural composition, biogenesis, and role of exosomes in the propagation of pathogenic proteins in NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). It highlights the potential of exosomal biomarkers for disease diagnosis and monitoring. The foundation for LC-MS-based analyses is discussed, focusing on isolation, purification, and characterization techniques essential for reliable proteomic and metabolomic studies. The LC-MS workflow, from protein and metabolite identification to quantitative proteomics, is detailed alongside the advantages of LC-MS in uncovering exosomal biomarkers. We delve into the application of LC-MS/MS in NDs research, showcasing its contributions to decoding disease pathology in AD, PD, and ALS by identifying specific exosomal biomarkers. Challenges such as the heterogeneity of exosome populations, variability in biofluid samples, and technical limitations in LC-MS analysis are critically examined. Finally, we discuss the future potential of LC-MS in advancing the diagnosis and treatment of NDs, emphasizing its transformative impact on biomarker discovery and personalized medicine.