Abstract
Early and accurate diagnosis of neurodegenerative diseases (NDDs) remains a significant challenge, hindering timely therapeutic interventions. This study aimed to identify novel protein signatures associated with the earliest stages of neurodegeneration using a comprehensive quantitative proteomics approach. Post-mortem brain tissue samples from regions critically affected in early neurodegeneration (e.g., hippocampus, prefrontal cortex) were collected from 20 individuals with confirmed early-stage NDD pathology and 20 age-matched neurologically healthy controls. Multiplexed tandem mass tag (TMT) labeling coupled with high-resolution liquid chromatography-mass spectrometry (LC-MS/MS) was employed to quantify protein abundance changes across the cohorts. Our analysis identified over 5,000 proteins, with 387 proteins demonstrating significant differential expression (p 1.5) in early-stage neurodegeneration compared to controls. Pathway enrichment analysis revealed alterations in processes related to synaptic function, mitochondrial energy metabolism, protein ubiquitination, and inflammatory responses, including microglial activation. Notably, several hitherto uncharacterized proteins and novel isoforms of known proteins were significantly dysregulated, forming distinct early-stage neurodegenerative signatures. These findings suggest that quantitative proteomics can uncover subtle yet critical molecular changes occurring at the nascent stages of NDDs, offering promising avenues for the development of early diagnostic biomarkers and targeted therapeutic strategies. Further validation in larger cohorts and different biofluids is warranted.
Keywords
Quantitative proteomics, Neurodegeneration, Biomarkers, Early detection, Protein signatures, Mass spectrometry, Microglia, Synaptic dysfunction