Abstract
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.
Highlights
Alzheimer’s disease (AD) accounts for 60-70% of all dementia in the elderly and imposes a heavy burden on society [1, 2]
After removing unannotated and duplicate genes, 6,847 out of 13,679 background genes were differentially expressed between AD and nondementia controls (Figure 1(a))
The results emerging from weight gene correlation network analysis (WGCNA) revealed that brown, blue, and turquoise modules were intimately associated with AD, the Differentially Expressed Genes (DEGs) of which were enriched in proteasome, cytokine-cytokine receptor interaction, glutamatergic
Summary
Alzheimer’s disease (AD) accounts for 60-70% of all dementia in the elderly and imposes a heavy burden on society [1, 2] This clinical entity is a slowly progressing brain disorder manifested by cognitive decline, behavioral abnormality, and psychiatric alteration [3]. The cell cycle is a tightly regulated process that, when reinitiated or undergoing failure of cell cycle arrest, may result in a pattern of programmed cell death termed as apoptosis [2, 7, 8] This unscheduled event in turn facilitates Aβ toxicity and tau hyperphosphorylation, to the formation of AD neuropathology [9, 10]
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