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

Show simple item record Konttinen, Henna Cabral-da-Silva, Mauricio e Castro Ohtonen, Sohvi Wojciechowski, Sara Shakirzyanova, Anastasia Caligola, Simone Giugno, Rosalba Ishchenko, Yevheniia Hernández, Damián Fazaludeen, Mohammad Feroze Eamen, Shaila Budia, Mireia Gómez Fagerlund, Ilkka Scoyni, Flavia Korhonen, Paula Huber, Nadine Haapasalo, Annakaisa Hewitt, Alex W. Vickers, James Smith, Grady C. Oksanen, Minna Graff, Caroline Kanninen, Katja M. Lehtonen, Sarka Propson, Nicholas Schwartz, Michael P. Pébay, Alice Koistinaho, Jari Ooi, Lezanne Malm, Tarja 2020-03-02T10:32:01Z 2020-03-02T10:32:01Z 2019-10-08
dc.identifier.citation Konttinen , H , Cabral-da-Silva , M E C , Ohtonen , S , Wojciechowski , S , Shakirzyanova , A , Caligola , S , Giugno , R , Ishchenko , Y , Hernández , D , Fazaludeen , M F , Eamen , S , Budia , M G , 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 , Pébay , A , Koistinaho , J , Ooi , L & 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 .
dc.identifier.other PURE: 126883304
dc.identifier.other PURE UUID: 28d27a01-3c2f-48db-a3f0-e30da801eb90
dc.identifier.other RIS: urn:BD263F66AB2331647914E862B6032ECE
dc.identifier.other WOS: 000489322400008
dc.identifier.other ORCID: /0000-0001-6559-1153/work/70951889
dc.description.abstract 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. en
dc.format.extent 15
dc.language.iso eng
dc.relation.ispartof Stem cell reports
dc.rights cc_by_nc_nd
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Alzheimer disease
dc.subject iPSC
dc.subject microglia
dc.subject phagocytosis
dc.subject mitochondria
dc.subject metabolism
dc.subject BETA
dc.subject MODEL
dc.subject PRESENILIN-1
dc.subject MACROPHAGES
dc.subject ACTIVATION
dc.subject 1182 Biochemistry, cell and molecular biology
dc.subject 3111 Biomedicine
dc.title PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia en
dc.type Article
dc.contributor.organization Neuroscience Center
dc.description.reviewstatus Peer reviewed
dc.relation.issn 2213-6711
dc.rights.accesslevel openAccess
dc.type.version draft

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