Alzheimer’s disease risk genes modulate interferon‐responsive microglia

Abstract

AbstractBackgroundHuman genetic studies and quantitative trait loci (eQTL) analyses have implicated microglia, the innate immune cells of the brain, as critical players in Alzheimer’s disease (AD). In response, the field has focused on defining microglial transcriptional states across many models of neurodegeneration. Integrating these studies, we find several microglial activation states commonly enriched in AD. These include Disease Associated Microglia, Antigen‐Presenting Microglia, and Interferon‐Responsive Microglia. To truly make use of this data, we now must move towards understanding the functional consequence of these microglial activation states and uncovering the mechanisms that drive changes in cell states during disease.MethodTo determine regulators of the interferon‐responsive microglial activation state, we performed a functional genomic screen using CRISPR interference (CRISPRi). To avoid bottlenecking of CRISPR guide RNAs and accommodate the large numbers of cells needed for screening, we implemented a novel transcription‐factor driven approach to differentiate iPSC‐derived microglia. After differentiation, microglia harboring individual gene knockdowns were primed with type I interferon and screened on expression of IFIT1, a key marker of the interferon‐responsive microglial state.ResultThese experiments have uncovered both canonical regulators of interferon signaling as well as novel regulators of the interferon‐responsive microglial state. Furthermore, several known AD risk genes were shown to inhibit microglial entry into this state, suggesting a potential mechanism whereby these nodes may influence disease risk.ConclusionRecent transcriptomic studies have uncovered significant heterogeneity of microglial states including the discovery of several disease associated states. However, it remains unclear whether these states represent beneficial, disease‐fighting functions or detrimental, disease‐promoting functions. Gaining the ability to selectively control entry into specific microglial states will allow novel investigations into how these specific microglial states interact with and guide disease trajectories.