Label‐Free Proteomic Profiling of the dvls2 (CL2006) Caenorhabditis elegans Alzheimer's Disease (AD) Model Reveals Conserved Molecular Signatures Shared With the Human AD Brain

TL;DR

This study uses a worm model of Alzheimer's to find shared protein changes with human AD, identifying eEF-2 as a key player.

Contribution

First proteomic characterization of the dvls2 (CL2006) C. elegans AD model with cross-species comparison to human AD data.

Findings

543 differentially regulated proteins were identified in the dvls2 (CL2006) strain.

eEF-2 was identified as a conserved key regulator in both human AD and the C. elegans model.

Shared molecular signatures include altered metabolism and protein homeostasis.

Abstract

Alzheimer's disease (AD) is the most common form of dementia, posing significant challenges to cognitive, emotional, social, and financial well‐being. The biochemical and molecular pathways associated with AD are complex, making it difficult to study and simulate in patients or through in vitro research. Thus, animal models play a crucial role in investigating the development and progression of AD. One widely used model in neuroscience studies is the free‐living nematode
Caenorhabditis elegans
(
C. elegans
). The development of transgenic animals has allowed for the construction of the dvls2 (CL2006)
C. elegans
strain, which constitutively expresses the amyloid beta (Aβ) peptide. This study conducted a proteomic analysis on the dvls2 (CL2006) strain. Also, a cross‐species comparative analysis was performed using microarray data from AD patients to identify genes with ontology in the dvls2 (CL2006). A total of 543 proteins were found to be differentially regulated in the dvls2 (CL2006) strain. Furthermore, in the analysis of the human datasets, 397 upregulated and 767 downregulated genes were identified. The differentially expressed genes (DEGs) were analyzed in Ortholist to identify their orthologs in
C. elegans
. Then, the orthologous genes in the dvls2 (CL2006) model were compared to the proteomic data, resulting in the identification of 29 upregulated and 24 downregulated proteins (DEPs). Functional enrichment analysis of DEPs revealed terms related to pyruvate, glucose, and glutamate metabolism, in addition to binding activities to unfolded proteins and ligases, highlighting the upregulation of chaperone and ubiquitination‐associated proteins. Protein–protein network (PPI) was performed for the human DEGs and DEPs of dvls2 (CL2006). Topological analyses of the networks were performed, revealing the following
C. elegans hub proteins: EEF‐2, ALH‐13, ENOL‐1, RPL‐2, TPI‐1, CTS‐1, RPL‐9, RPL‐23, CCT‐1, and RPS‐8. eEF‐2 was identified as a key regulator of the human AD PPI and dvls2 (CL2006). Modules were analyzed in the networks, and the presence of key regulators was identified. This study provides the first proteomic characterization of the AD model dvls2 (CL2006) and a cross‐species comparative analysis with data from AD individuals, supporting the use of dvls2 (CL2006) in AD studies.

Cross‐species analysis combining
C. elegans
proteomics and Alzheimer's disease brain transcriptomics reveals shared alterations in stress response, metabolism, and protein homeostasis, highlighting eEF‐2 as a conserved key regulator.

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