PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia Konttinen, H, Cabral-da-Silva, MEC, Ohtonen, S, Wojciechowski, S, Shakirzyanova, A, Caligola, S, Giugno, R, Ishchenko, Y, Hernández, D, Fazaludeen, MF, Eamen, S, Budia, MG, Fagerlund, I, Scoyni, F, Korhonen, P, Huber, N, Haapasalo, A, Hewitt, AW, Vickers, J, Smith, GC, Oksanen, M, Graff, C, Kanninen, KM, Lehtonen, S, Propson, N, Schwartz, MP, Pébay, 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. Attached Files Name Description MIMEType Size Downloads Title PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia Author(s) Konttinen, H Cabral-da-Silva, MEC Ohtonen, S Wojciechowski, S Shakirzyanova, A Caligola, S Giugno, R Ishchenko, Y Hernández, D Fazaludeen, MF Eamen, S Budia, MG Fagerlund, I Scoyni, F Korhonen, P Huber, N Haapasalo, A Hewitt, AW Vickers, J Smith, GC Oksanen, M Graff, C Kanninen, KM Lehtonen, S Propson, N Schwartz, MP Pébay, A Koistinaho, J Ooi, L Malm, T Journal name Stem Cell Reports Volume number 13 Issue number 4 Start page 669 End page 683 Total pages 15 Publisher Cell Press Place of publication Cambridge, Mass. Publication date 2019 ISSN 2213-6711 Keyword(s) Science & Technology Life Sciences & Biomedicine Cell & Tissue Engineering Cell Biology PLURIPOTENT STEM-CELLS ALZHEIMERS-DISEASE PRECURSOR PROTEIN BETA DIFFERENTIATION MODEL HEMATOPOIESIS PRESENILIN-1 MACROPHAGES ACTIVATION APOE APPswe Alzheimer disease E9 PSEN1Δ iPSC metabolism microglia mitochondria phagocytosis Summary 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. Language eng DOI 10.1016/j.stemcr.2019.08.004 Field of Research 0601 Biochemistry and Cell Biology 1103 Clinical Sciences HERDC Research category C1 Refereed article in a scholarly journal Free to Read? Yes Persistent URL http://hdl.handle.net/10536/DRO/DU:30164040 Document type: Journal Article Collections: Faculty of Health School of Medicine Open Access Collection Related Links Link Description Link to full-text (open access)   Connect to Elements publication management system Go to link with your DU access privileges     Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved. Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au. Versions Version Filter Type Thu, 10 Mar 2022, 07:05:56 EST Thu, 10 Mar 2022, 16:01:38 EST Thu, 10 Mar 2022, 16:03:58 EST Wed, 06 Apr 2022, 08:56:18 EST Wed, 20 Apr 2022, 16:40:11 EST Wed, 20 Apr 2022, 16:48:12 EST Wed, 20 Apr 2022, 17:18:38 EST Filtered Full Citation counts:   Cited 52 times in TR Web of Science Cited 56 times in Scopus Search Google Scholar Access Statistics: 8 Abstract Views, 0 File Downloads  -  Detailed Statistics Created: Thu, 10 Mar 2022, 07:05:56 EST