Human microglia differentially respond to ß-amyloid, tau, and combined Alzheimer's disease pathologies in vivo

Recent studies have identified important species-dependent differences in the response of microglia to beta-amyloid pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occurs in Alzheimer’s Disease (AD) remains unclear. We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling. Combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct “rod” morphology in human microglia. The Rod morphology could be induced with type-I interferon treatment in vitro. We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.