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

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dc.contributor.author Konttinen, Henna
dc.contributor.author Cabral-da-Silva, Mauricio e Castro
dc.contributor.author Ohtonen, Sohvi
dc.contributor.author Wojciechowski, Sara
dc.contributor.author Shakirzyanova, Anastasia
dc.contributor.author Caligola, Simone
dc.contributor.author Giugno, Rosalba
dc.contributor.author Ishchenko, Yevheniia
dc.contributor.author Hernández, Damián
dc.contributor.author Fazaludeen, Mohammad Feroze
dc.contributor.author Eamen, Shaila
dc.contributor.author Budia, Mireia Gómez
dc.contributor.author Fagerlund, Ilkka
dc.contributor.author Scoyni, Flavia
dc.contributor.author Korhonen, Paula
dc.contributor.author Huber, Nadine
dc.contributor.author Haapasalo, Annakaisa
dc.contributor.author Hewitt, Alex W.
dc.contributor.author Vickers, James
dc.contributor.author Smith, Grady C.
dc.contributor.author Oksanen, Minna
dc.contributor.author Graff, Caroline
dc.contributor.author Kanninen, Katja M.
dc.contributor.author Lehtonen, Sarka
dc.contributor.author Propson, Nicholas
dc.contributor.author Schwartz, Michael P.
dc.contributor.author Pébay, Alice
dc.contributor.author Koistinaho, Jari
dc.contributor.author Ooi, Lezanne
dc.contributor.author Malm, Tarja
dc.date.accessioned 2020-03-02T10:32:01Z
dc.date.available 2020-03-02T10:32:01Z
dc.date.issued 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 . https://doi.org/10.1016/j.stemcr.2019.08.004
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.identifier.uri http://hdl.handle.net/10138/312606
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 PLURIPOTENT STEM-CELLS
dc.subject ALZHEIMERS-DISEASE
dc.subject PRECURSOR PROTEIN
dc.subject BETA
dc.subject DIFFERENTIATION
dc.subject MODEL
dc.subject HEMATOPOIESIS
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.doi https://doi.org/10.1016/j.stemcr.2019.08.004
dc.relation.issn 2213-6711
dc.rights.accesslevel openAccess
dc.type.version draft

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