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Stem Cell Reports. 2019 Oct 8;13(4):669-683. doi: 10.1016/j.stemcr.2019.08.004. Epub 2019 Sep 12.

PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia.

Author information

1
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland.
2
School of Chemistry and Molecular Bioscience, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
3
Department of Computer Science, University of Verona, Verona 37134, Italy.
4
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC 3002, Australia; Department of Surgery, the University of Melbourne, Melbourne, VIC 3002, Australia; Department of Anatomy and Neuroscience, the University of Melbourne, Melbourne, VIC 3002, Australia.
5
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, VIC 3002, Australia; Department of Surgery, the University of Melbourne, Melbourne, VIC 3002, Australia; School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, VIC 7005, Australia.
6
Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, TAS 7000, Australia.
7
Department NVS, Division of Neurogeriatrics, Karolinka Institutet, Stockholm 17176, Sweden; Theme Aging, Genetics Unit, Karolinska University Hospital-Solna, Stockholm 17176, Sweden.
8
Department of Molecular and Cell Biology and the Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
9
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
10
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland; Neuroscience Center, University of Helsinki, Helsinki 00014, Finland.
11
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70211, Finland. Electronic address: tarja.malm@uef.fi.

Abstract

Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, 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 PSEN1ΔE9 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.

KEYWORDS:

APOE; APPswe; Alzheimer disease; E9; PSEN1Δ; iPSC; metabolism; microglia; mitochondria; phagocytosis

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