Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis
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Dysfunction of microglia, the brain's immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals.
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iPSC-derived microglial-like cells were generated using established protocols.
“iPSC-derived microglial-like cells were generated using established protocols [64,65].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [64]
Human induced pluripotent stem cell microglia-like cells harboring mutations in TREM2 show distinct defects in phagocytosis.
“Indeed, human induced pluripotent stem cell microglia-like cells harboring mutations in TREM2 show distinct defects in phagocytosis [47].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [47]
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- Authors
- Garcia-Reitboeck, P., Phillips, A., Piers, T. M., Villegas-Llerena, C., Butler, M., Mallach, A., Rodrigues, C., Arber, C. E., Heslegrave, A., Zetterberg, H., Neumann, H., Neame, S., Houlden, H., Hardy, J., & Pocock, J. M.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- University of Bonn (DE)
- Eisai (United Kingdom) (GB)
- Corresponding author
- Pocock, Jennifer M.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 24
- Issue
- 9
- Pages
- 2300-2311
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6130048
- OpenAlex
- W2889172944
- Cited by
- 162
- References
- 45
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 20 · 2023: 11 · 2022: 28 · 2021: 26 · 2020: 29 · 2019: 20 · 2018: 1
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- University College London
- Medical Research Council (MR/M02492X/1)
- Horizon 2020 Framework Programme
- European Federation of Pharmaceutical Industries and Associations
- Alzheimer's Society
- Innovative Medicines Initiative (115976)
- Alzheimerâs Research UK
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- TREM2, missense mutations, Nasu-Hakola disease, microglia, phagocytosis, apoptotic bodies, neurodegeneration, cell survival, cytokine production, microglial migration
- MeSH terms
- Humans, Membrane Glycoproteins, Phagocytosis, Receptors, Immunologic, Microglia, Mutation, Missense, Induced Pluripotent Stem Cells
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