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Identification of Unstable Network Modules Reveals Disease Modules Associated with the Progression of Alzheimer’s Disease

Author

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  • Masataka Kikuchi
  • Soichi Ogishima
  • Tadashi Miyamoto
  • Akinori Miyashita
  • Ryozo Kuwano
  • Jun Nakaya
  • Hiroshi Tanaka

Abstract

Alzheimer’s disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.

Suggested Citation

  • Masataka Kikuchi & Soichi Ogishima & Tadashi Miyamoto & Akinori Miyashita & Ryozo Kuwano & Jun Nakaya & Hiroshi Tanaka, 2013. "Identification of Unstable Network Modules Reveals Disease Modules Associated with the Progression of Alzheimer’s Disease," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-1, November.
  • Handle: RePEc:plo:pone00:0076162
    DOI: 10.1371/journal.pone.0076162
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    References listed on IDEAS

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    1. Tao Lu & Ying Pan & Shyan-Yuan Kao & Cheng Li & Isaac Kohane & Jennifer Chan & Bruce A. Yankner, 2004. "Gene regulation and DNA damage in the ageing human brain," Nature, Nature, vol. 429(6994), pages 883-891, June.
    2. Brookmeyer, R. & Gray, S. & Kawas, C., 1998. "Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset," American Journal of Public Health, American Public Health Association, vol. 88(9), pages 1337-1342.
    3. Johannes Gräff & Damien Rei & Ji-Song Guan & Wen-Yuan Wang & Jinsoo Seo & Krista M. Hennig & Thomas J. F. Nieland & Daniel M. Fass & Patricia F. Kao & Martin Kahn & Susan C. Su & Alireza Samiei & Nadi, 2012. "An epigenetic blockade of cognitive functions in the neurodegenerating brain," Nature, Nature, vol. 483(7388), pages 222-226, March.
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