A systematic analysis of genomic changes in Tg2576 mice

Abstract

The pathogenesis of AD is complicated and may involve alterations in a large number of genes/proteins and disruption to their anfractuous interactions, rather than an alteration in a single gene/protein. Several studies, including some microarray analysis, have been performed using Tg2576 mice, and consequently hundreds of differentially expressed genes have been identified, especially regarding plasticity-related genes. However, few studies have focused on the co-expression patterns of associated pathways with their core genes and transcription factors (TF). Published microarray data from Stein's article can be obtained from the Gene Expression Omnibus database, accession No. GSE1556. The data were assessed using the Bioconductor software packages, and genes with a >2.0-fold differential expression were further analyzed by statistical tests. A testing correction method by false discovery rate was applied with a p < 0.05 cut-off in our statistical tests. Gene Ontology (GO) analysis, Positional Gene Enrichment (PGE) analysis, and Gene Set Enrichment analysis (GSEA) were performed as previously described. Thus, in this study, we applied systematic biology approaches with published microarray data and revealed that (1) Aβ overload induces neuronal apoptosis mainly through a mitochondrial-mediated apoptotic pathway; (2) that several genes important for axon guidance are misregulated in Tg2576 mice, and thus may be responsible for synaptic degeneration; and (3) that TF and TF-binding motifs disturbances might participate in the inflammatory process. Numerous studies have identified that Aβ plays a significant role in the onset and progression of AD. One mechanism by which Aβ can induce apoptosis and impair synaptic connections is through the disturbance of mitochondrial function, leading to dysregulation in Ca 2+ homeostasis and reactive oxygen species production. Understanding the downstream mechanisms of the mitochondrial-mediated apoptotic pathway may uncover potential therapeutic targets for AD. The findings of this study also suggest that transcription is a significant functional group in the analysis of gene expression profiles. Modulators of inflammatory processes and neuronal Ca 2+ signaling, which were impaired by some disturbances TF and TF-binding motifs, may be potential therapeutic targets for AD.