Journal
STEM CELL REPORTS
Volume 13, Issue 4, Pages 669-683Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2019.08.004
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Funding
- University of Eastern Finland
- Academy of Finland [301234, 298071, 305516, 315459]
- European Union's Horizon 2020 research and innovation program [643417]
- Finnish Instrumentarium Science Foundation
- Yrjo Jahnsson's Foundation [20187070]
- National Health and Medical Research Council of Australia (NHMRC) [APP1125796]
- NHMRC Boosting Dementia Research Leadership Fellowship [APP1135720]
- Yulgilbar Alzheimer's Research Program
- DHB Foundation
- C.F. Leung Memorial Trust
- Brain Foundation
- Dementia Australia
- National Health and Medical Research Council [1154389]
- Australian Research Council Future Fellowship [FT140100047]
- University of Melbourne
- UEF Cell and Tissue Imaging Unit, University of Eastern Finland
- Academy of Finland (AKA) [305516, 298071, 305516, 301234, 298071, 301234] Funding Source: Academy of Finland (AKA)
- National Health and Medical Research Council of Australia [1154389] Funding Source: NHMRC
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Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1 Delta E9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create 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 PSEN1 Delta E9 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.
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