PLX071012

GSE135707: PSEN1E9, APPswe and APOE4 confer disparate phenotypes in human iPSC-derived microglia

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Here we elucidate the effect of Alzheimers disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1E9 and APPswe, on functionality of human microglia. We present a physiologically relevant high-yield protocol for producing human microglia-like cells (iMGLs) from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to recreate microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality whereas PSEN1E9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD. SOURCE: Tarja Malm (tarja.malm@uef.fi) - Tarja Malm Lab University of Eastern Finland