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

Jay M. Yarbro, Xian Han, Abhijit Dasgupta, Ka Yang, Danting Liu, Him K. Shrestha, Masihuz Zaman, Zhen Wang, Kaiwen Yu, Dong Geun Lee, David Vanderwall, Mingming Niu, Huan Sun, Boer Xie, Ping-Chung Chen, Yun Jiao, Xue Zhang, Zhiping Wu, Surendhar R. Chepyala, Yingxue Fu, Yuxin Li, Zuo-Fei Yuan, Xusheng Wang, Suresh Poudel, Barbora Vagnerova, Qianying He, Andrew Tang, Patrick T. Ronaldson, Rui Chang, Gang Yu, Yansheng Liu and Junmin Peng ()
Additional contact information
Jay M. Yarbro: St. Jude Children’s Research Hospital
Xian Han: St. Jude Children’s Research Hospital
Abhijit Dasgupta: St. Jude Children’s Research Hospital
Ka Yang: St. Jude Children’s Research Hospital
Danting Liu: St. Jude Children’s Research Hospital
Him K. Shrestha: St. Jude Children’s Research Hospital
Masihuz Zaman: St. Jude Children’s Research Hospital
Zhen Wang: St. Jude Children’s Research Hospital
Kaiwen Yu: St. Jude Children’s Research Hospital
Dong Geun Lee: St. Jude Children’s Research Hospital
David Vanderwall: St. Jude Children’s Research Hospital
Mingming Niu: St. Jude Children’s Research Hospital
Huan Sun: St. Jude Children’s Research Hospital
Boer Xie: St. Jude Children’s Research Hospital
Ping-Chung Chen: St. Jude Children’s Research Hospital
Yun Jiao: St. Jude Children’s Research Hospital
Xue Zhang: St. Jude Children’s Research Hospital
Zhiping Wu: St. Jude Children’s Research Hospital
Surendhar R. Chepyala: St. Jude Children’s Research Hospital
Yingxue Fu: St. Jude Children’s Research Hospital
Yuxin Li: St. Jude Children’s Research Hospital
Zuo-Fei Yuan: St. Jude Children’s Research Hospital
Xusheng Wang: University of Tennessee Health Science Center
Suresh Poudel: St. Jude Children’s Research Hospital
Barbora Vagnerova: University of Arizona
Qianying He: University of Arizona
Andrew Tang: University of Arizona
Patrick T. Ronaldson: University of Arizona
Rui Chang: University of Arizona
Gang Yu: University of Texas Southwestern Medical Center
Yansheng Liu: Yale University School of Medicine
Junmin Peng: St. Jude Children’s Research Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Murine models of Alzheimer’s disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. Here we present the comprehensive, age-dependent brain proteome and phosphoproteome across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata and prioritized 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). Our analysis of 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, identifies potential targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.

Date: 2025
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DOI: 10.1038/s41467-025-56853-3

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