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Cited by 191Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsPluripotent Stem Cells Research

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

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Konttinen, Henna, Cabral-da-Silva, Mauricio e Castro, Ohtonen, Sohvi, Wojciechowski, Sara, Shakirzyanova, Anastasia, Caligola, Simone, Giugno, Rosalba, Ishchenko, Yevheniia +22 more·2019·Stem Cell Reports
DOI 10.1016/j.stemcr.2019.08.004PMC PMC6829767
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Abstract

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 Ca 2+ 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.

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  • The iPSC lines used were characterized for genetic stability and pluripotency markers.

    “Characterization for genetic stability and pluripotency markers of these iPSCs was previously documented in studies using iPSC differentiation into astrocytes and microglia for the screening of AD-associated glial aberrancies [26,27].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [26]

    The Results section (Figure 1B; page unavailable) reports measuring pluripotency markers in iPSCs. Experimental Procedures, “Generation and Maintenance of iPSCs” (page unavailable), says several lines were previously characterized but identifies others as previously uncharacterized. Our copy does not establish that the lines were characterized for genetic stability. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Differentiated microglia expressed microglial markers and had phagocytic ability.

    “Upon differentiation, we obtained microglia revealing markers and phagocytic ability, as reported by Konttinen and colleagues [26] (Figure 4B,C).”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [26]

  • Generated microglial cells had a typical microglial signature including CD11b, TMEM119, Iba1 and CX3CR1, and demonstrated phagocytic properties.

    “Here, we generated microglial cells with the typical microglial signature, including microglia-specific markers (CD11b, TMEM119, Iba1 and CX3CR1), which also demonstrated phagocytic properties, in accordance with similar studies [21,26].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [26]

  • Decreased immunofluorescence and increased gene expression of TREM2 in MG-AD suggest TREM2 imbalance.

    “Here, its decreased immunofluorescence and increased gene expression in MG-AD suggest TREM2 imbalance, as Konttinen and colleagues reported for the same cells [26].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [26]

    The Results section on iMGL differentiation (page unavailable) reports TREM2 immunostaining as evidence of microglial identity. It does not report decreased TREM2 immunofluorescence, increased TREM2 gene expression, or an imbalance in MG-AD cells. Searches for those terms found no passage addressing the claimed changes. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

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Authors
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.
Affiliations
  • University of Eastern Finland (FI)
  • University of Verona (IT)
  • The University of Melbourne (AU)
  • University of Tasmania (AU)
  • University of Wollongong (AU)
  • Karolinska University Hospital (SE)
  • Baylor College of Medicine (US)
  • University of Wisconsin–Madison (US)
Corresponding author
Malm, Tarja
ORCID
Venue
Stem Cell Reports
Publisher
Elsevier BV
Published
2019-10
Volume
13
Issue
4
Pages
669-683
ISSN
2213-6711 (ISSN-L)
DOI
10.1016/j.stemcr.2019.08.004
PMC
PMC6829767
OpenAlex
W2972433621
Cited by
191
References
17
Citations by year
2026: 19 · 2025: 27 · 2024: 24 · 2023: 24 · 2022: 36 · 2021: 31 · 2020: 28 · 2019: 1
FWCI
10.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UTAS Research Repository (acceptedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
  • Research Online (University of Wollongong) (submittedVersion)
  • Deakin Research Online (Deakin University) (submittedVersion)
  • Figshare (submittedVersion, cc-by-nc-nd)
  • Figshare (submittedVersion, cc-by)
Funders
  • Brain Foundation
  • European Commission
  • Yrjö Jahnssonin Säätiö (20187070)
  • Turun Yliopisto
  • EU Joint Programme – Neurodegenerative Disease Research
  • University of Melbourne
  • Itä-Suomen Yliopisto
  • Horizon 2020 Framework Programme (643417)
  • National Health and Medical Research Council (APP1135720, APP1125796, 1154389)
  • State Government of Victoria
  • Academy of Finland (301234, 315459, 305516, 298071)
  • Australian Research Council (FT140100047)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
Alzheimer's disease, microglia, induced pluripotent stem cells, iPSC-derived microglia, APOE ε4, APPswe, yolk sac, phagocytosis, microglial migration, cytokine production, microglial dysfunction
MeSH terms
Alzheimer Disease, Calcium, Cell Differentiation, Cells, Cultured, Hematopoiesis, Humans, Mutation, Phagocytosis, Phenotype, Cytokines, Amyloid beta-Protein Precursor, Microglia, Inflammation Mediators, Chemokines, Apolipoprotein E4, Presenilin-1, Induced Pluripotent Stem Cells, Proteolysis

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