Time dynamics of protein complexes in the AD11 transgenic mouse model for Alzheimer’s disease like pathology

BMC Neuroscience

Concettina Guerra²  Giovanni Felici¹  Fabio Cumbo¹  Paola Bertolazzi¹  Antonino Cattaneo³  Rossella Brandi⁴  Mara D’Onofrio⁴  Ivan Arisi⁴ 

[1]Istituto di Analisi dei Sistemi ed Informatica “Antonio Ruberti” (IASI-CNR), Rome, Italy

[2]College of Computing, Georgia Institute of Technology, Atlanta, GA, USA

[3]Scuola Normale Superiore, Piazza dei Cavalieri 7, Pisa, 56126, Italy

[4]Genomics Facility, European Brain Research Institute (EBRI) Rita Levi-Montalcini, Via del Fosso di Fiorano, 64, Rome, 00143, Italy

关键词: AD11 mouse model;    Protein complex;    Network;    Correlation;    Protein-protein interaction;    Neurodegeneration;    NGF;    Alzheimers disease;   

Others  :  1210190
DOI  :  10.1186/s12868-015-0155-5

 received in 2014-12-01, accepted in 2015-03-11,  发布年份 2015

【 摘 要 】

Background

Many approaches exist to integrate protein-protein interaction data with other sources of information, most notably with gene co-expression data, to obtain information on network dynamics. It is of interest to look at groups of interacting gene products that form a protein complex. We were interested in applying new tools to the characterization of pathogenesis and dynamic events of an Alzheimer’s-like neurodegenerative model, the AD11 mice, expressing an anti-NGF monoclonal antibody. The goal was to quantify the impact of neurodegeneration on protein complexes, by measuring the correlation between gene expression data by different metrics.

Results

Data were extracted from the gene expression profile of AD11 brain, obtained by Agilent microarray, at 1, 3, 6, 15 months of age. For genes coding proteins in complexes, the correlation matrix of pairwise expression was computed. The dynamics between correlation matrices at different time points was evaluated: paired T-test between average correlation levels and a normalized Euclidean distance with z-score. We unveiled a differential wiring of interactions in a set of complexes, whose network structure discriminates between transgenic and control mice. Furthermore, we analyzed the dynamics of gene expression values, by looking at changes in gene-to-gene correlation over time and identified those complexes that exhibit a different timedependent behaviour between transgenic and controls. The most significant changes in correlation dynamics are concentrated in the early stage of disease, with higher correlation in AD11 mice compared to controls. Many complexes go through dynamic changes over time, showing the role of the dysfunctional immunoproteasome, as early neurodegenerative disease event. Furthermore, this analysis shows key events in the neurodegeneration process of the AD11 model, by identifying significant differences in co-expression values of other complexes, such as parvulin complex, with a role in protein misfolding and proteostasis, and of complexes involved in transcriptional mechanisms.

Conclusions

We have proposed a novel approach to analyze the network structure of protein complexes, by two different measures to evaluate the dynamics of gene-gene correlation matrices from gene expression profiles. The methodology was able to investigate the re-organization of interactions within protein complexes in the AD11 model of neurodegeneration.

【 授权许可】

   
2015 Arisi et al.; licensee BioMed Central.

【 图 表 】

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