Discovery of Proteoforms Associated With Alzheimer's Disease Through Quantitative Top-Down Proteomics

Fulcher, James M.; Ives, Ashley N.; Tasaki, Shinya; Kelly, Shane S.; Williams, Sarah M.; Fillmore, Thomas L.; Zhou, Mowei; Moore, Ronald J.; Qian, Wei-Jun; Paša-Tolić, Ljiljana; Yu, Lei; Oveisgharan, Shahram; Bennett, David A.; De Jager, Philip L.; Petyuk, Vladislav A.

doi:10.1016/j.mcpro.2025.100983

Title: Discovery of Proteoforms Associated With Alzheimer's Disease Through Quantitative Top-Down Proteomics

Journal Article · Mon May 05 00:00:00 UTC 2025 · Molecular and Cellular Proteomics

DOI: https://doi.org/10.1016/j.mcpro.2025.100983 · OSTI ID:2572296

^[1]; Ives, Ashley N. ^[1]; Tasaki, Shinya ^[2];

^[3]; Williams, Sarah M. ^[1]; Fillmore, Thomas L. ^[3];

^[4]; Moore, Ronald J. ^[3];

^[3]; Paša-Tolić, Ljiljana ^[1]; Yu, Lei ^[2];

^[2]; Bennett, David A. ^[2]; De Jager, Philip L. ^[5];

^[3]

Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)
Rush Univ. Medical Center, Chicago, IL (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Zhejiang Univ., Hangzhou (China)
Columbia Univ., New York, NY (United States)

The complex nature of Alzheimer's disease (AD) and its heterogenous clinical presentation has prompted numerous large-scale -omic analyses aimed at providing a global understanding of the pathophysiological processes involved. AD involves isoforms, proteolytic products, and posttranslationally modified proteins such as amyloid beta (Aβ) and microtubule-associated protein tau. Top-down proteomics directly measures these species and thus, offers a comprehensive view of pathologically relevant proteoforms that are difficult to analyze using traditional proteomic techniques. Here, we broadly explored associations between proteoforms and clinicopathological traits of AD by deploying a quantitative top-down proteomics approach across frontal cortex of 103 subjects selected from the ROS and MAP cohorts. The approach identified 1213 proteins and 11,782 proteoforms, of which 154 proteoforms had at least one significant association with a clinicopathological phenotype. One important finding included identifying Aβ C-terminal truncation state as the key property for differential association between amyloid plaques and cerebral amyloid angiopathy. Furthermore, various N-terminally truncated forms of Aβ had noticeably stronger association with amyloid plaques and global cognitive function. Additionally, we discovered six VGF neuropeptides that were positively associated with cognitive function independent of pathological burden. The database of brain cortex proteoforms provides a valuable context for functional characterization of the proteins involved in AD and other late-onset brain pathologies.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2572296

Report Number(s):: PNNL-SA-205981

Journal Information:: Molecular and Cellular Proteomics, Journal Name: Molecular and Cellular Proteomics Journal Issue: 6 Vol. 24; ISSN 1535-9476

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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