Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific
Pablo Garcia-Reitboeck1, Alexandra Phillips2, Thomas M Piers3
1Department 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.
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.
Insights
Homozygous TREM2 mutations impair microglial function, impacting brain health and leading to Nasu-Hakola disease. These cellular deficits highlight TREM2
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglial dysfunction is implicated in neurodegenerative diseases.
- Nasu-Hakola disease (NHD) is an early-onset dementia caused by homozygous TREM2 mutations.
Purpose of the Study:
- To investigate the functional consequences of TREM2 missense mutations (T66M, W50C) found in NHD patients.
- To characterize patient-derived induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) harboring these mutations.
Main Methods:
- Generated iPSC-MGLCs from NHD patients with specific TREM2 mutations.
- Assessed TREM2 expression and secretion.
- Evaluated LPS-mediated cytokine secretion, cell survival, and phagocytic capacity (apoptotic bodies, E. coli, zymosan).
- Analyzed apoptotic cell-induced cytokine release and migration.
Main Results:
- TREM2 expression and secretion were reduced in iPSC-MGLCs with TREM2 missense mutations.
- Cell survival was significantly reduced in mutant lines compared to controls.
- Phagocytosis of apoptotic bodies was markedly impaired, while phagocytosis of E. coli and zymosan remained unaffected.
- TREM2 mutations altered apoptotic cell-induced cytokine release and migration.
Conclusions:
- TREM2 missense mutations lead to specific functional deficits in microglia-like cells.
- Impaired phagocytosis of apoptotic bodies and altered responses to pathogenic signals contribute to NHD pathogenesis.
- iPSC-MGLCs serve as a valuable model for studying TREM2-related neurodegenerative diseases.
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