Comparative gene regulatory network analysis in Alzheimer’s disease and major depressive disorder

Abstract

SummaryMajor depressive disorder and Alzheimer’s disease are two prevalent and devastating disorders that still lack effective treatment. Despite distinct disease phenotypes, these two disorders are characterized by similar neuroinflammatory processes. However, it is not clear to what extent these processes are shared. To compare pathways and their regulators affected in Alzheimer’s disease and depression, we adopted a systems biology approach. Consensus gene regulatory networks were built from RNA-seq data with GENIE3, CLR and Lemon-Tree. The two consensus networks were functionally characterized and compared to one another. Further, single-cell gene regulatory networks were constructed with SCENIC, to further characterize the regulatory programs active in specific cell types. In both disorders, aberrations in immune mechanisms and microglial activation were found, controlled by the same transcription factors (IKZF1, IRF8, NFATC2, RUNX1, SPI1, and TAL1). These transcription factors have been implicated in Alzheimer’s disease before, while only one has been associated with depression hitherto. Moreover, in Alzheimer, dysfunctions in mitochondria, the proteasome and myelination were discovered. In depression, astrocyte function, GABA receptor signaling, and transport across the blood-brain barrier were aberrated. These disrupted pathways and transcription factors should be further investigated and might be used to develop novel therapies for neuroinflammatory disorders.