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Stem Cell Reports. 2018 Apr 10;10(4):1294-1307. doi: 10.1016/j.stemcr.2018.03.003. Epub 2018 Mar 29.

Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia.

Author information

1
The Gurdon Institute, ARUK Stem Cell Research Centre and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
2
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany; DZNE, German Center for Neurodegenerative Diseases, Tübingen 72076, Germany.
3
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
4
Wellcome Trust Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
5
The Gurdon Institute, ARUK Stem Cell Research Centre and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: rick@gurdon.cam.ac.uk.

Abstract

The derivation of microglia from human stem cells provides systems for understanding microglial biology and enables functional studies of disease-causing mutations. We describe a robust method for the derivation of human microglia from stem cells, which are phenotypically and functionally comparable with primary microglia. We used stem cell-derived microglia to study the consequences of missense mutations in the microglial-expressed protein triggering receptor expressed on myeloid cells 2 (TREM2), which are causal for frontotemporal dementia-like syndrome and Nasu-Hakola disease. We find that mutant TREM2 accumulates in its immature form, does not undergo typical proteolysis, and is not trafficked to the plasma membrane. However, in the absence of plasma membrane TREM2, microglia differentiate normally, respond to stimulation with lipopolysaccharide, and are phagocytically competent. These data indicate that dementia-associated TREM2 mutations have subtle effects on microglia biology, consistent with the adult onset of disease in individuals with these mutations.

KEYWORDS:

Nasu-Hakola disease; TREM2; dementia; frontotemporal dementia; iPSC-microglia; microglia; neuroinflammation

PMID:
29606617
PMCID:
PMC5998752
DOI:
10.1016/j.stemcr.2018.03.003
[Indexed for MEDLINE]
Free PMC Article

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