A core transcriptional signature of human microglia: derivation and utility in describing region-dependent alterations associated with Alzheimer’s disease

Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to better characterize their function in health and disease. Studies in mouse, have applied transcriptome-wide profiling of microglia to reveal key features of microglial ontogeny, functional profile and phenotypic diversity. Whilst similar in many ways, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, little consistency was observed between studies. Hence, we set out to define a conserved microglia signature of the human central nervous system (CNS), through a comprehensive meta-analysis of existing transcriptomic resources. Nine datasets derived from cells and tissue, isolated from different regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified. Comparison of individual microglia clusters showed 249 genes highly conserved between them. This core gene signature included all known markers and improves upon published microglial signatures. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region-specific alterations in aging and Alzheimers disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations in the contribution of human microglia towards the CNS in health and disease.\n\nTable of ContentsMain points O_LIPublished microglial transcriptional signatures in mouse and human show poor consensus.\nC_LIO_LIA core transcriptional signature of human microglia with 249 genes was derived and found conserved across brain regions, encompassing the CNS.\nC_LIO_LIThe signature revealed region-dependent microglial alterations in Alzheimers, highlighting susceptible CNS regions and the involvement of TYROBP signaling.\nC_LI