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Cited by 41Alzheimer's disease research and treatmentsAdvanced Proteomics Techniques and ApplicationsDementia and Cognitive Impairment Research

Human and mouse proteomics reveals the shared pathways in Alzheimer’s disease and delayed protein turnover in the amyloidome

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Yarbro, Jay M., Han, Xian, Dasgupta, Abhijit, Yang, Ka, Liu, Danting, Shrestha, Him K., Zaman, Masihuz, Wang, Zhen +24 more·2025·Nature Communications
DOI 10.1038/s41467-025-56853-3PMC PMC11814087

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Abstract

Abstract Murine models of Alzheimer’s disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. We comprehensively profiled age-dependent brain proteome and phosphoproteome (n > 10,000 for both) across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata, and prioritized novel components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Determining the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including Aβ-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identify potential new targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.

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Authors
Yarbro, J. M., Han, X., Dasgupta, A., Yang, K., Liu, D., Shrestha, H. K., Zaman, M., Wang, Z., Yu, K., Lee, D. G., Vanderwall, D., Niu, M., Sun, H., Xie, B., Chen, P.-C., Jiao, Y., Zhang, X., Wu, Z., Chepyala, S. R., Fu, Y., Li, Y., Yuan, Z.-F., Wang, X., Poudel, S., Vagnerova, B., He, Q., Tang, A., Ronaldson, P. T., Chang, R., Yu, G., Liu, Y., & Peng, J.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • University of Tennessee Health Science Center (US)
  • University of Arizona (US)
  • The University of Texas Southwestern Medical Center (US)
  • Yale University (US)
Corresponding author
Peng, Junmin
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-02-11
Volume
16
Issue
1
Pages
1533-1533
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-56853-3
PMC
PMC11814087
OpenAlex
W4407375763
Cited by
41
References
127
Citations by year
2026: 26 · 2025: 15
FWCI
26.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
ALSAC
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloidosis, amyloid plaques, 5xFAD mice, brain proteome, phosphoproteome, protein turnover, tau pathology

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