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Gene network of interaction between Alzheimer's disease and lipid metabolism reconstructed by ANDSystem

Name
Olga
Surname
Saik
Scientific organization
ICG SB RAS
Academic degree
no
Position
Junior Researcher
Scientific discipline
Life Sciences & Medicine
Topic
Gene network of interaction between Alzheimer's disease and lipid metabolism reconstructed by ANDSystem
Abstract
Nowadays it becomes obvious that Alzheimer's disease (AD) is very complex. Recently it was shown that lipid metabolism (LM) is involved in the progression of Alzheimer's disease. The mechanisms linking lipid metabolism and Alzheimer disease are still not well understood. The goal of this study was to reconstruct and analyze gene network linking lipid metabolism and Alzheimer disease. This knowledge may give a deeper understanding of molecular-genetic basis of Alzheimer disease.
Keywords
Gene network, Alzheimer's disease, lipid metabolism, ANDSystem
Summary

Gene network of interaction between Alzheimer's disease and lipid metabolism reconstructed by ANDSystem

Saik O.V.1, Ignatieva E.V. 1, Demenkov P.S. 1, Afonnikov D.A. 1, Ivanisenko V.A. 1 and Rogaev E.I. 1,2,3

1 Center for Brain Neurobiology and Neurogenetics Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk, Russia.  

2Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia

3Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, USA

 

Motivation and Aim: Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by β-amyloid plaque formation in human brain. The formation of amyloid plaques is modulated by cellular cholesterol. The cholesterol level in brain is increased during the AD progression (Hannaoui et al., 2014). Nevertheless the mechanisms linking the lipid metabolism and AD are not yet well understood. The goal of this study was to reconstruct and analyze gene network connecting the lipid metabolism and AD. This study may identify novel molecular pathway elements for AD and can contribute to improvement of existing AD therapy approaches.

Materials and methods: Gene list associated with lipid metabolism was formed based on the information from scientific publications, Coremine system (makes statistical assessment for terms co-occurrence in publications) and Gene Ontology annotation. List of genes associated with Alzheimer's disease was extracted from GWAS Catalog, OMIM, GeneCards databases, MeShops and CoreMine systems and ANDSystem (Ivanisenko et al., 2015). Gene networks reconstruction was performed by ANDSystem that utilize automated literature mining approach (text-mining). Information on drug targets was extracted from DrugBank database. Gene Ontology enrichment analysis was performed by DAVID. Betweenness centrality of a protein in a network was calculated by R package igraph. Statistical significance difference of distributions was assessed by t-test and Mann–Whitney U test implemented in Python library SciPy.

Results:

Reconstruction of gene network associated with lipid metabolism.

List of 1451 genes associated with lipid metabolism was obtained by manual analysis of scientific publications and automated methods from Coremine and Gene Ontology annotation and used for gene network reconstruction by ANDSystem. In the reconstructed gene network associated with lipid metabolism 1029 proteins were connected by 7734 interactions.

Reconstruction of gene network associated with Alzheimer's disease.

List of 884 genes associated with Alzheimer's disease was extracted from databases (GWAS Catalog, OMIM, GeneCards), MeShops and CoreMine systems and ANDSystem. In the reconstructed gene network associated with AD 595 proteins were connected by 6626 interactions.

Reconstruction and analysis of gene networks describing interaction between lipid metabolism and Alzheimer disease.

We found that 150 proteins are common for AD and LM gene networks. Among them 100 proteins are known drug targets. It is reasonable to speculate that intake of such drugs could potentially cause adverse effects related to AD or vice versa can imply a potential therapeutic molecule. For example, pravastatin has a neuroprotective effect (Corrao et al., 2013).

To investigate if genes associated with Alzheimer's disease are core in the lipid metabolism network we compared the distributions of betweenness centrality of genes associated with AD and LM simultaneously and genes associated with LM. Betweenness centrality of a node in a network is equal to the number of shortest paths from all vertices to all other nodes that pass through that node. A node with high betweenness centrality has a large influence on the network. Comparing the betweenness centrality distribution for proteins associated with AD and LM with the same distribution built on LM proteins demonstrated significant differences from each other (p<0.0001). The average numbers of betweenness centrality for proteins associated with AD and LM was 1479 while for all proteins associated with LM it was only 523. Thus we can speculate that genes associated with Alzheimer's disease play essential role in lipid metabolism network. Several studies indicated that cholesterol metabolism may contribute to AD (Hannaoui et al., 2014). We found that the “cholesterol metabolic process” cluster is statistically significant enriched by proteins associated with AD (p-value<0.0001).

There is evidence that some diseases associated with alterations of lipid metabolism, such as obesity, weight loss (Leboucher et al., 2013), atherosclerosis (Ismailov, 2013), dyslipidemias and diabetes mellitus (Akomolafe et al., 2006) can influence AD pathogenesis. Statistical analysis showed that these diseases have more common genes with AD than it could be expected (p<0.0001).

 

This work has been done by the finance support of the Government of the Russian (Project №14.B25.31.0033, Resolution No.220 Federation of April 9, 2010).

 

References:

Akomolafe, A., Beiser, A., Meigs, J. B., Au, R., Green, R. C., Farrer, L. A., ... & Seshadri, S. (2006). Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Archives of neurology, 63(11), 1551-1555.

Corrao, G., Ibrahim, B., Nicotra, F., Zambon, A., Merlino, L., Pasini, T. S., ... & Mancia, G. (2013). Long-term use of statins reduces the risk of hospitalization for dementia. Atherosclerosis, 230(2), 171-176.

Hannaoui, S., Shim, S. Y., Cheng, Y. C., Corda, E., & Gilch, S. (2014). Cholesterol Balance in Prion Diseases and Alzheimer’s Disease. Viruses, 6(11), 4505-4535.

Ismailov, R. M. (2013). Circle of Willis atherosclerosis, Alzheimer’s disease and the Dean number. World journal of cardiology, 5(10), 394.

Ismailov, R. M. (2013). Circle of Willis atherosclerosis, Alzheimer’s disease and the Dean number. World journal of cardiology, 5(10), 394.

Ivanisenko, V. A., Saik, O. V., Ivanisenko, N. V., Tiys, E. S., Ivanisenko, T. V., Demenkov, P. S., & Kolchanov, N. A. (2015). ANDSystem: an Associative Network Discovery System for automated literature mining in the field of biology. BMC systems biology, 9(Suppl 2), S2.

Leboucher, A., Laurent, C., Fernandez-Gomez, F. J., Burnouf, S., Troquier, L., Eddarkaoui, S., ... & Blum, D. (2013). Detrimental effects of diet-induced obesity on ? pathology are independent of insulin resistance in ? transgenic mice. Diabetes, 62(5), 1681-1688.