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

Autor:	Yarbro JM; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; These authors contributed equally., Han X; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; These authors contributed equally., Dasgupta A; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Current address: Department of Computer Science and Engineering, SRM University AP, Andhra Pradesh 522240, India.; These authors contributed equally., Yang K; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; These authors contributed equally., Liu D; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Shrestha HK; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Zaman M; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Wang Z; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Yu K; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Lee DG; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Vanderwall D; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Niu M; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Sun H; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Xie B; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Chen PC; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Jiao Y; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Zhang X; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Wu Z; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Fu Y; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Li Y; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Yuan ZF; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Wang X; Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA., Poudel S; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Vagnerova B; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., He Q; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Tang A; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Ronaldson PT; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Chang R; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA., Yu G; Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Liu Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.; Yale Cancer Research Institute, Yale University School of Medicine, West Haven, CT, 06516, USA., Peng J; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 25. Date of Electronic Publication: 2024 Oct 25.
DOI:	10.1101/2024.10.25.620263
Abstrakt:	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.
Databáze:	MEDLINE
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