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

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http://hdl.handle.net/10138/312606

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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

Titel: PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia
Författare: 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
Upphovmannens organisation: Neuroscience Center
Datum: 2019-10-08
Språk: eng
Sidantal: 15
Tillhör serie: Stem cell reports
ISSN: 2213-6711
DOI: https://doi.org/10.1016/j.stemcr.2019.08.004
Permanenta länken (URI): http://hdl.handle.net/10138/312606
Abstrakt: 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.
Subject: Alzheimer disease
iPSC
microglia
phagocytosis
mitochondria
metabolism
PLURIPOTENT STEM-CELLS
ALZHEIMERS-DISEASE
PRECURSOR PROTEIN
BETA
DIFFERENTIATION
MODEL
HEMATOPOIESIS
PRESENILIN-1
MACROPHAGES
ACTIVATION
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
Referentgranskad: Ja
Licens: cc_by_nc_nd
Användningsbegränsning: openAccess
Parallelpublicerad version: draft


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