Network Analysis of a Comprehensive Knowledge Repository Reveals a Dual Role for Ceramide in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common cause of senile dementia. Many inflammatory factors such as amyloid-β and pro-inflammatory cytokines are known to contribute to the inflammatory response in the AD brain. Sphingolipids are widely known to have roles in the pathogenesis of inflammatory diseases, where the precise roles for sphingolipids in inflammation-associated pathogenesis of AD are not well understood. Here we performed a network analysis to clarify the importance of sphingolipids and to model relationships among inflammatory factors and sphingolipids in AD. In this study, we have updated sphingolipid signaling and metabolic cascades in a map of AD signaling networks that we named "AlzPathway," a comprehensive knowledge repository of signaling pathways in AD. Our network analysis of the updated AlzPathway indicates that the pathways related to ceramide are one of the primary pathways and that ceramide is one of the important players in the pathogenesis of AD. The results of our analysis suggest the following two prospects about inflammation in AD: (1) ceramide could play important roles in both inflammatory and anti-inflammatory pathways of AD, and (2) several factors such as Sphingomyelinase and Siglec-11 may be associated with ceramide related inflammation and anti-inflammation pathways in AD. In this study, network analysis of comprehensive knowledge repository reveals a dual role for ceramide in AD. This result provides a clue to clarify sphingolipids related inflammatory and anti-inflammatory pathways in AD.

Fig 1. Overview of AlzPathway 3 overlaid with sphingolipid-related canonical pathway annotations.

AlzPathway 3 consists of 1,384 molecules, 1,127 reactions, and 138 phenotypes. Purple lines are newly added relations involving sphingolipids.

Fig 2. Binary-relation notation AlzPathway 3 and the key molecules.

(a) The top 50 high-centrality relations as the highlighted primary pathway of AlzPathway. Circles are nodes in AlzPathway 3. Lines are edges between nodes. As represented, red lines have high edge betweeness centrality and blue lines have low. (b) The top 10 high-betweenness centrality nodes and their centrality.

Fig 3. Factors potentially associated with ceramide and inflammation.

(a) Extracted sub-network from the binary-relation notation AlzPathway 3. The simplified binary-relation notation AlzPathway 3 consists of two hops from “Ceramide” and “Inflammation.” (b) The top 50 high-centrality relations of the simplified binary-relation notation AlzPathway 3.