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

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.

阿尔茨海默病（Alzheimer’s disease, AD）是老年痴呆最常见的病因。已知诸多炎症因子，如β淀粉样蛋白（amyloid-β）与促炎细胞因子，均参与阿尔茨海默病患者脑组织的炎症反应过程。鞘脂（sphingolipids）在炎症性疾病的发病机制中发挥调控作用已被广泛证实，但目前学界对其在阿尔茨海默病炎症相关发病机制中的具体功能仍尚不明确。本研究通过构建网络分析，以明确鞘脂类的重要性，并建模解析阿尔茨海默病中炎症因子与鞘脂类之间的相互关联。本研究对阿尔茨海默病信号网络图谱中的鞘脂信号与代谢级联通路进行了更新，该图谱被命名为"AlzPathway"——阿尔茨海默病信号通路综合知识库。我们对更新后的AlzPathway进行网络分析后发现，与神经酰胺（ceramide）相关的通路是核心通路之一，而神经酰胺亦是阿尔茨海默病发病机制中的关键调控因子之一。本研究分析结果针对阿尔茨海默病的炎症机制提出两项展望：其一，神经酰胺可能同时参与阿尔茨海默病的促炎与抗炎通路；其二，鞘磷脂酶（Sphingomyelinase）、Siglec-11等若干因子或与阿尔茨海默病中神经酰胺相关的炎症及抗炎通路存在关联。本研究通过对综合知识库开展网络分析，揭示了神经酰胺在阿尔茨海默病中的双重调控作用。该研究结果为阐明阿尔茨海默病中鞘脂类相关的炎症与抗炎通路提供了重要线索。