iPSC villages to understand neuroimmune changes in Alzheimer's disease

Using village for iMG in vitro and xenograft models, we show that microglia from up to 50 different donors grown in villages recapitulate microglia states observed in vitro and in vivo. We found that donors are equally distributed across multiple transcriptional signatures, including disease-associated microglia transcriptional signatures. This method also allows us to study microglia function across multiple donors. For example, we confirmed the defects in phagocytosis in TREM2R47H carrying donors. Finally, villages can be used to identify new variants altering key microglia characteristics. In a pool of 25 cell lines, we identified TMEM106B, a lysosomal protein involved in neurodegenerative disease, as a modifier of microglia phagocytosis CONCLUSION: Microglia villages can be used to study the impact of LOAD accurately and uncover phenotypes across multiple patients, including males and females and patients from various genetic ancestry. This method will allow us to bridge the gap between transcriptomic signature and microglia function to identify regulators of microglia states and functions across a large number of patients.