Basic Science and Pathogenesis.

Background: Replacement, Reduction, and Refinement (3R) guidelines propose the use of alternative models to study human diseases. These models have high homology and are less onerous compared to rodents, which dominate Alzheimer's disease (AD) research. However, it is still necessary to investigate whether evolutionary components are conserved among AD models cross-species. Thus, we aimed to determine similar and different core molecular programs and biological processes in alternative and mouse models of AD.

Methods: We searched the Gene Expression Omnibus (GEO) repository for available RNa-sequencing studies of alternative (Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio) and mouse (Mus musculus) models of amyloidosis. The following datasets were selected for alternative (GSE198684, GSE109489, GSE158233) and mouse (GSE186710 and GSE144746) models of AD. According to the species, we selected the brain (hippocampus), head, or whole body as samples. Data was downloaded using the GEOquery package and the differentially expressed genes were defined as having FDR- adjusted p-value < 0.05. Using the R Studio and Cytoscape software, we grouped DEGs into clusters of gene ontology for biological processes (GOBPs) according to their function.

Results: A greater number of DEGs were shared between D. rerio and mouse models of amyloidosis when compared to other species (Figure 1). By comparing alternative models, C. elegans has more DEG-intersections with D. melanogaster than with D. rerio (Figure 1). Regarding biological processes, more overlap of GOBPs was found between D. melanogaster and M. musculus (Figure 2). C. elegans, despite having present DEGs in common with D. rerio and M. musculus, did not share GOBP terms with these vertebrates, but only with D. melanogaster (Figure 2). The shared biological processes conserved among the species were classically associated with AD pathology, such as protein misfolding response, immune and inflammatory systems, neurotransmission, and metabolic processes (Figure 3).

Conclusions: The findings suggest that alternative models share transcriptomic similarities with mouse models of amyloidosis. Thus, these models may serve to accelerate the understanding of amyloid-related pathophysiological processes and the development of innovative therapeutics in AD.