A Systems Biology Approach for the Identification of Active Molecular Pathways During the Progression of Alzheimer's Disease.

MOTIVATION: In the last years, systems-level network-based approaches have gained ground in the research field of systems biology. These approaches are based on the analysis of high-throughput sequencing studies, which are rapidly increasing year by year. Nowadays, the single-cell RNA-sequencing, an optimized next-generation sequencing (NGS) technology that offers a better understanding of the function of an individual cell in the context of its microenvironment, prevails. RESULTS: Toward this direction, a method is developed in which active molecular subpathways are recorded during the time evolution of the disease under study. This method operates for expression profiling by high-throughput sequencing data. Its capability is based on capturing the temporal changes of local gene communities that form a disease-perturbed subpathway. The aforementioned methods are applied to real data from a recent study that uses single-cell RNA-sequencing data related with the progression of neurodegeneration. More specific, microglia cells were isolated from the hippocampus of a mouse model with Alzheimer's disease-like phenotypes and severe neurodegeneration and of control mice at multiple time points during progression of neurodegeneration. Our analysis offers a different view for neurodegeneration progression under the perspective of systems biology. CONCLUSION: Our approach into the molecular perspective using a temporal tracking of active pathways in neurodegeneration at single-cell resolution may offer new insights for designing new efficient strategies to treat Alzheimer's and other neurodegenerative diseases.

Detecting Common Pathways and Key Molecules of Neurodegenerative Diseases from the Topology of Molecular Networks.

MotivationNeurodegenerative diseases (NDs), including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, occur as a result of neurodegenerative processes. Thus, it has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels. However, traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Discovering this overlap offers hope for therapeutic advances that could ameliorate many ND simultaneously. In parallel, in the last decade, systems biology approaches have become a reliable choice in complex disease analysis for gaining more delicate biological insights and have enabled the comprehension of the higher order functions of the biological systems.ResultsToward this orientation, we developed a systems biology approach for the identification of common links and pathways of ND, based on well-established and novel topological and functional measures. For this purpose, a molecular pathway network was constructed, using molecular interactions and relations of four main neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease). Our analysis captured the overlapped subregions forming molecular subpathways fully enriched in these four NDs. Also, it exported molecules that act as bridges, hubs, and key players for neurodegeneration concerning either their topology or their functional role.ConclusionUnderstanding these common links and central topologies under the perspective of systems biology and network theory and greater insights are provided to uncover the complex neurodegeneration processes.