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PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia


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Konttinen, H, Cabral-da-Silva, MeC, Ohtonen, S, Wojciechowski, S, Shakirzyanova, A, Caligola, S, Giugno, R, Ishchenko, Y, Hernandez, D, Fazaludeen, MF, Eamen, S, Budia, MG, Fagerlund, I, Scoyni, F, Korhonen, P, Huber, N, Haapasalo, A, Hewitt, AW ORCID: 0000-0002-5123-5999, Vickers, J ORCID: 0000-0001-5671-4879, Smith, GC, Oksanen, M, Graff, C, Kanninen, KM, Lehtonen, S, Propson, N, Schwartz, MP, Pebay, A, Koistinaho, J, Ooi, L and Malm, T 2019 , 'PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia' , Stem Cell Reports, vol. 13, no. 4 , pp. 669-683 , doi: 10.1016/j.stemcr.2019.08.004.

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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.

Item Type: Article
Authors/Creators:Konttinen, H and Cabral-da-Silva, MeC and Ohtonen, S and Wojciechowski, S and Shakirzyanova, A and Caligola, S and Giugno, R and Ishchenko, Y and Hernandez, D and Fazaludeen, MF and Eamen, S and Budia, MG and Fagerlund, I and Scoyni, F and Korhonen, P and Huber, N and Haapasalo, A and Hewitt, AW and Vickers, J and Smith, GC and Oksanen, M and Graff, C and Kanninen, KM and Lehtonen, S and Propson, N and Schwartz, MP and Pebay, A and Koistinaho, J and Ooi, L and Malm, T
Keywords: APOE, APPswe, Alzheimer disease, E9, PSEN1Δ, iPSC, metabolism, microglia, mitochondria, phagocytosis
Journal or Publication Title: Stem Cell Reports
Publisher: Cell Press
ISSN: 2213-6711
DOI / ID Number: 10.1016/j.stemcr.2019.08.004
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Copyright 2019 The Authors. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

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