The human microglia responsome: a resource for microglia states in health and disease

Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human enriched microglial cells from 67 different donors (N = 398 samples, primarily aged >60 years) at the gene and transcript level. We show that enriched microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We define specific enriched microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimer’s disease (AD) (genetic) studies and enriched microglia. Together, we provide a comprehensive transcriptomic resource of the human microglia responsome.