137583 - PSEN1&%23916;E9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia.pdf (4.92 MB)
PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia
journal contribution
posted on 2023-05-20, 11:11 authored by 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, Alexander HewittAlexander Hewitt, James VickersJames Vickers, Smith, GC, Oksanen, M, Graff, C, Kanninen, KM, Lehtonen, S, Propson, N, Schwartz, MP, Pebay, A, Koistinaho, J, Ooi, L, Malm, THere 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.
History
Publication title
Stem Cell ReportsVolume
13Issue
4Pagination
669-683ISSN
2213-6711Department/School
Menzies Institute for Medical ResearchPublisher
Cell PressPlace of publication
United StatesRights statement
Copyright 2019 The Authors. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/Repository Status
- Open