Journal article
PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia
H Konttinen, MEC Cabral-da-Silva, S Ohtonen, S Wojciechowski, A Shakirzyanova, S Caligola, R Giugno, Y Ishchenko, D Hernández, MF Fazaludeen, S Eamen, MG Budia, I Fagerlund, F Scoyni, P Korhonen, N Huber, A Haapasalo, AW Hewitt, J Vickers, GC Smith Show all
Stem Cell Reports | CELL PRESS | Published : 2019
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 ..
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Grants
Awarded by Itä-Suomen Yliopisto
Funding Acknowledgements
This work is part of an EU Joint Program -Neurodegenerative Disease Research (JPND) project. This study was funded by the University of Eastern Finland, the Academy of Finland under grant nos. 301234, 298071, 305516, and 315459 (FiNeFTD), the European Union's Horizon 2020 research and innovation program under grant agreement no. 643417, Finnish Instrumentarium Science Foundation, and Yrjo Jahnsson's Foundation grant no. 20187070, the National Health and Medical Research Council of Australia (NHMRC, APP1125796), an NHMRC Boosting Dementia Research Leadership Fellowship (APP1135720), Yulgilbar Alzheimer's Research Program, the DHB Foundation, the C.F. Leung Memorial Trust, the Brain Foundation, Dementia Australia, a National Health and Medical Research Council Practitioner Fellowship (AWH) and Senior Research Fellowship (AP, 1154389), an Australian Research Council Future Fellowship (AP, FT140100047), the University of Melbourne and Operational Infrastructure Support from the Victorian Government. We thank Matti Viitala for skin biopsies, Louise A. Rooney, Sophie Chevalier, and Maciej Daniszewski for the characterization of iPSC lines, Vikrant Singh for virtual karyotype help, and Helena H. Liang for culture of biopsies to fibroblasts. We also thank Finnish Functional Genomics Center (FFGC), University of Turku and Abo Akademi and Biocenter Finland, for RNA sequencing. This work was carried out with the support of UEF Cell and Tissue Imaging Unit, University of Eastern Finland.