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

Authors

Henna Konttinen, University of Eastern Finland
Mauricio E Castro Cabral Da Silva, University of WollongongFollow
Sohvi Ohtonen, University of Eastern Finland
Sara Wojciechowski, University of Eastern Finland
Anastasia Shakirzyanova, University of Eastern Finland
Simone Caligola, University of Verona
Rosalba Giugno, University of Verona
Yevheniia Ishchenko, University of Eastern Finland
Damian Hernandez, University of Melbourne
Mohammad Fazaludeen, University of Eastern Finland
Shaila Eamen, University of Eastern Finland
Mireia Budia, University of Eastern Finland
Ilkka Fagerlund, University of Eastern Finland
Flavia Scoyni, University of Eastern Finland
Paula Korhonen, University of Eastern Finland
Nadine Huber, University of Eastern Finland
Annakaisa Haapasalo, University of Eastern Finland
Alex W. Hewitt, Victorian Clinical Genetics Services, University of Tasmania, University of MelbourneFollow
James Vickers, University of Tasmania
Grady Smith, University of Wollongong
Minna Oksanen, University of Eastern Finland
Caroline Graff, Karolinska University Hospital-Solna, Karolinka Institutet
Katja Kanninen, University of Eastern Finland
Sarka Lehtonen, University of Eastern Finland
Nicholas Propson, Baylor College Of Medicine
Michael Schwartz, University of Wisconsin-Madison
Alice Pebay, University of Melbourne, O'Brien Institute, St Vincent's Melbourne, Royal Victorian Eye and Ear HospitalFollow
Jari Koistinaho, University of Eastern Finland, University of Helsinki
Lezanne Ooi, University of WollongongFollow
Tarja Malm, University of Eastern Finland

RIS ID

139157

Publication Details

Konttinen, H., e Castro Cabral-Da-Silva, M., Ohtonen, S., Wojciechowski, S., Shakirzyanova, A., Caligola, S., Giugno, R., Ishchenko, Y., Hernandez, D., Fazaludeen, M., Eamen, S., Budia, M. Gomez., Fagerlund, I., Scoyni, F., Korhonen, P., Huber, N., Haapasalo, A., Hewitt, A. W., Vickers, J., Smith, G. C., Oksanen, M., Graff, C., Kanninen, K. M., Lehtonen, S., Propson, N., Schwartz, M. P., Pebay, A., Koistinaho, J., Ooi, L. & Malm, T. (2019). PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Stem Cell Reports, 13 (4), 669-683.

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.

Grant Number

NHMRC/1125796

Grant Number

NHMRC/1135720