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Integrating the Alzheimer's disease proteome and transcriptome: a comprehensive network model of a complex disease.

ABSTRACT: Network models combined with gene expression studies have become useful tools for studying complex diseases like Alzheimer's disease. We constructed a "Core" Alzheimer's disease protein interaction network by human curation of the primary literature. The Core network consisted of 775 nodes and 2,204 interactions. To our knowledge, this is the most comprehensive and accurate protein interaction network yet constructed for Alzheimer's disease. An "Expanded" network was computationally constructed by adding additional proteins that interacted with Core network proteins, and consisted of 4,945 nodes and 26,064 interactions. We then mapped existing gene expression studies to the Core network. This combined data model identified the MAPK/ERK pathway and clathrin-mediated receptor endocytosis as key pathways in Alzheimer's disease. Important proteins in the MAPK/ERK pathway that interacted in the Core network formed a downregulated cluster of nodes, whereas clathrin and several clathrin accessory proteins that interacted in the Core network formed an upregulated cluster of nodes. The MAPK/ERK pathway is a key component in synaptic plasticity and learning, processes disrupted in Alzheimer's. Clathrin and clathrin adaptor proteins are involved in the endocytosis of the APP protein that can lead to increased intracellular levels of amyloid beta peptide, contributing to the progression of Alzheimer's.

SUBMITTER: Hallock P

PROVIDER: S-EPMC3275800 | biostudies-other | 2012 Jan-Feb

REPOSITORIES: biostudies-other

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Integrating the Alzheimer's disease proteome and transcriptome: a comprehensive network model of a complex disease.

Hallock Peter P Thomas Michael A MA

Omics : a journal of integrative biology 20120101 1-2

Network models combined with gene expression studies have become useful tools for studying complex diseases like Alzheimer's disease. We constructed a "Core" Alzheimer's disease protein interaction network by human curation of the primary literature. The Core network consisted of 775 nodes and 2,204 interactions. To our knowledge, this is the most comprehensive and accurate protein interaction network yet constructed for Alzheimer's disease. An "Expanded" network was computationally constructed ...[more]

PMID: 22321014

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Project description:There is an urgent need to improve the translational validity of Alzheimer's disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease-neuronal synapse/signaling and lysosome/stress response-were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.

Project description:Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer's disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organization of these protein networks and their relationship to clinicopathological traits of disease. In this proof-of-concept study, we performed a systems-based sub-proteomic analysis of membrane-enriched post-mortem brain samples from pathology-free control, AsymAD, and AD brains (n = 6 per group). Label-free mass spectrometry based on peptide ion intensity was used to quantify the 18 membrane-enriched fractions. Differential expression and weighted protein co-expression network analysis (WPCNA) were then used to identify and characterize modules of co-expressed proteins most significantly altered between the groups. We identified a total of 27 modules of co-expressed membrane-associated proteins. In contrast to the unfractionated proteome, these networks did not map strongly to cell-type specific markers. Instead, these modules were principally organized by their associations with a wide variety of membrane-bound compartments and organelles. Of these, the mitochondrion was associated with the greatest number of modules, followed by modules linked to the cell surface compartment. In addition, we resolved networks with strong associations to the endoplasmic reticulum, Golgi apparatus, and other membrane-bound organelles. A total of 14 of the 27 modules demonstrated significant correlations with clinical and pathological AD phenotypes. These results revealed that the proteins within individual compartments feature a heterogeneous array of AD-associated expression patterns, particularly during the preclinical stages of disease. In conclusion, this systems-based analysis of the membrane-associated AsymAD brain proteome yielded a unique network organization highly linked to cellular compartmentalization. Further study of this membrane-associated proteome may reveal novel insight into the complex pathways governing the earliest stages of disease.

Dataset Information

Integrating the Alzheimer's disease proteome and transcriptome: a comprehensive network model of a complex disease.

Publications

Integrating the Alzheimer's disease proteome and transcriptome: a comprehensive network model of a complex disease.

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