Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer's disease animal model

Xiao-Rui Cheng,Yue-Ying Zhao,Sheng-Qi Wang,Xiao-Chen Bo,Gui-Rong Zhang,Wen-Xia Zhou,Yong-Xiang Zhang,Huang Huang,Yue Zheng,Xiu-Liang Cui,Peng Li

doi:10.3389/fnagi.2013.00065

Abstract

Harboring the behavioral and histopathological signatures of Alzheimer's disease (AD), senescence accelerated mouse-prone 8 (SAMP8) mice are currently considered a robust model for studying AD. However, the underlying mechanisms, prioritized pathways and genes in SAMP8 mice linked to AD remain unclear. In this study, we provide a biological interpretation of the molecular underpinnings of SAMP8 mice. Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age-matched SAMR1 mice at 2, 6, and 12 months of age using cDNA microarray analysis. On the basis of PPI, MetaCore and the co-expression network, we constructed a distinct genetic sub-network in the brains of SAMP8 mice. Next, we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice. We found abnormal gene expression of RAF1, MAPT, PTGS2, CDKN2A, CAMK2A, NTRK2, AGER, ADRBK1, MCM3AP, and STUB1, which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice. Specifically, we found microRNAs, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b, that might regulate the expression of nodes in the sub-network. Taken together, these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro-pathogenesis in SAMP8 mice from a systems perspective.

Highlights

Alzheimer’s disease (AD) is a complex neurodegenerative disease
We found that the gene expression profile in the hippocampus of senescence accelerated mouse prone-8 (SAMP8) mice were different from SAMR1 mice at three different ages (Table 1)
After constructing the tissue-specific protein-protein interaction (PPI) subnetwork, we used 81 differentially expressed genes as seed genes to identify the PPI sub-network in SAMP8 mice. These results showed that the sub-network of the hippocampus and cerebral cortex inferred from PPI contained 105 genes, in which 25 genes were AD-related according to AlzGene (Bertram et al, 2007) and the p-value was 3.744E14 (Figure 2) (Supplement Table 2)

Summary

Introduction

Alzheimer’s disease (AD) is a complex neurodegenerative disease. Despite extensive research, the causal chain of mechanisms underlying AD remains unknown. Investigators have developed new therapies and have tested in detail, the structural (Gutierrez-Cuesta et al, 2007; del Valle et al, 2012; Li et al, 2012), functional (Sureda et al, 2006; Tajes et al, 2008; Lou et al, 2012; Yamaguchi et al, 2012) and behavioral consequences (Gong et al, 2008; Shi et al, 2010b; Shih et al, 2010; Chang et al, 2012; Kanno et al, 2012; Lopez-Ramos et al, 2012; Lou et al, 2012; Orejana et al, 2012; Dobarro et al, 2013; Huang et al, 2013; Sawano et al, 2013) of AD-associated pathology based on SAMP8 mice, little progress has been made with regard to the patho-physiological mechanisms of SAMP8 mice, and the underlying causes of the AD-like phenotype in SAMP8 mice remain unknown

Methods

Results

Discussion

Conclusion