Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis

Pablo Garcia-Reitboeck; Alexandra Phillips; Thomas M Piers; Claudio Villegas-Llerena; Matt Butler; Anna Mallach; Celia Rodrigues; Charles E Arber; Amanda Heslegrave; Henrik Zetterberg; Harald Neumann; Stephen Neame; Henry Houlden; John Hardy; Jennifer M Pocock

doi:10.1016/j.celrep.2018.07.094

Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis

Cell Rep. 2018 Aug 28;24(9):2300-2311. doi: 10.1016/j.celrep.2018.07.094.

Authors

Affiliations

¹ Department of Neuroinflammation, University College London Institute of Neurology, London WC1N 1PJ, UK; Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 1PJ, UK.
² Department of Neuroinflammation, University College London Institute of Neurology, London WC1N 1PJ, UK.
³ Department of Neuroinflammation, University College London Institute of Neurology, London WC1N 1PJ, UK; Eisai:UCL Therapeutic Innovation Group, University College London Institute of Neurology, London WC1N 1PJ, UK.
⁴ Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 1PJ, UK.
⁵ Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 1PJ, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg 41345, Sweden.
⁶ Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, Bonn 53127, Germany.
⁷ Neurology Business Group, Hatfield Research Laboratories, Neurology Innovation Centre, Eisai Limited, Hatfield, AL10 9SN, UK.
⁸ Department of Neuroinflammation, University College London Institute of Neurology, London WC1N 1PJ, UK. Electronic address: [email protected].

Abstract

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.

Keywords: Alzheimer disease; Nasu-Hakola disease; TREM2; cytokine; induced pluripotent stem cells; microglia; phagocytosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Induced Pluripotent Stem Cells / metabolism*
Membrane Glycoproteins / genetics*
Membrane Glycoproteins / metabolism
Microglia / metabolism*
Mutation, Missense*
Phagocytosis
Receptors, Immunologic / genetics*
Receptors, Immunologic / metabolism

Substances

Membrane Glycoproteins
Receptors, Immunologic
TREM2 protein, human

Grants and funding

MR/M02492X/1/MRC_/Medical Research Council/United Kingdom