Proteomics

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CZE-MS/MS-based quantitative top-down proteomics reveals significant proteoform differences between healthy and Alzheimer's disease human brains

ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and pathological protein aggregation. Comprehensive protein characterization of human brains of AD patients and comparison with healthy samples is critical for pursuing a better understanding of the molecular mechanisms that drive AD progression. Although many large-scale bottom-up proteomics studies of AD brains have been conducted, there are limited top-down proteomics (TDP) studies of human AD brains. This study employs CZE-MS/MS-based label-free quantitative TDP to profile proteoform differences in postmortem brain tissues from AD patients and healthy controls. Using a robust size exclusion chromatography (SEC) fractionation-CZE-MS/MS platform, we identified 3,191 unique proteoforms, uncovering distinct proteoform signatures between AD and healthy subjects. Principal component analysis (PCA) and hierarchical clustering revealed clear segregation of AD samples, driven by disease-specific changes in proteoform abundance . Notably, AD tissues exhibited elevated phosphorylation and combinatorial post-translational modifications (PTMs), including hyperphosphorylated tau and modified neurogranin proteoforms, which are implicated in synaptic dysfunction and neurodegeneration. Bidirectional regulation of proteoforms from key proteins such as Calmodulin-1 and MAPT further highlights the functional divergence in AD pathogenesis. Pathway analysis linked upregulated proteoforms in AD to amyloid fibril formation and microtubule disruption, while healthy samples were enriched for synaptic transmission and axogenesis pathways. These findings underscore the critical role of proteoform-specific alterations in AD pathology, offering new insights into molecular mechanisms and potential therapeutic targets.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Liangliang Sun  

LAB HEAD: Liangliang Sun

PROVIDER: PXD065459 | Pride | 2025-11-21

REPOSITORIES: Pride

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ALZ_1_3_1.raw Raw
ALZ_1_3_1_ms2_toppic_proteoform_single.tsv Tabular
ALZ_1_3_2.raw Raw
ALZ_1_3_2_ms2_toppic_proteoform_single.tsv Tabular
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Publications

Coupling CZE, Liquid-Phase Ion Mobility, to MS/MS for Quantitative Top-Down Proteomics: Revealing Significant Proteoform Differences Between Healthy and Alzheimer's Disease Brains.

Falamarzi Askarani Mehrdad M   Fang Fei F   Counts Scott E SE   Sun Liangliang L  

Proteomics 20250914

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and pathological protein aggregation. Comprehensive quantitative proteomics of brain tissues from AD patients is critical for pursuing a better understanding of the molecular mechanisms that drive AD progression. Here, we present one of the first quantitative top-down proteomics (TDP) studies of postmortem cortex samples from AD patients and healthy controls to profile their proteoform differences by coup  ...[more]

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