Integrative Functional Genomic Analysis of Molecular Signatures and Mechanistic Pathways in the Cell Cycle Underlying Alzheimer's Disease

OBJECTIVE: Alzheimer's disease (AD) is associated with cell cycle reentry of mature neurons that subsequently undergo degeneration. This study is aimed to identify key regulators of the cell cycle and their underlying pathways for developing optimal treatment of AD. METHODS: RNA sequencing data were profiled to screen for differentially expressed genes in the cell cycle. Correlation of created modules with AD phenotype was computed by weight gene correlation network analysis (WGCNA). Signature genes for trophic factor receptors were determined using Pearson correlation coefficient (PCC) analysis. RESULTS: Among the 13,679 background genes, 775 cell cycle genes and 77 trophic factor receptors were differentially expressed in AD versus nondementia controls. Four coexpression modules were constructed by WGCNA, among which the turquoise module had the strongest correlation with AD. According to PCC analysis, 10 signature trophic receptors most strongly interacting with cell cycle genes were filtered and subsequently displayed in the global regulatory network. Further cross-talking pathways of signature receptors, such as glutamatergic synapse, long-term potentiation, PI3K-Akt, and MAPK signaling pathways, were identified. CONCLUSIONS: Our findings highlighted the mechanistic pathways of signature trophic receptors in cell cycle perturbation underlying AD pathogenesis, thereby providing new molecular targets for therapeutic intervention in AD.